Compositions and methods for inhibiting nuclear receptor subfamily 1 group h member 3 (nr1h3) expression

ABSTRACT

Oligonucleotides are provided herein that inhibit NR1H3 expression. Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders and/or conditions associated with NR1H3 expression.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to European Patent Applications 21213711.1, filed Dec. 10, 2021 and 21186366.7, filed Jul. 19, 2021, and claims priority to U.S. Provisional Patent Application 63/176,814, filed Apr. 19, 2021; the contents of which are incorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 19, 2022, is named 210010US02_SeqList.txt and is 700 kilobytes in size.

BACKGROUND

The liver plays a critical role in the metabolism of lipids. Abnormalities in normal hepatic lipid metabolism are associated with the development of various liver diseases or disorders such as non-alcoholic fatty liver disease (NAFLD) and its subsequent progression to non-alcoholic steatohepatitis (NASH) and potentially other advanced liver abnormalities.

NAFLD is one of the most common liver diseases, with increasing prevalence worldwide (Loomba R., & Sanyal A. J. NAT. REV. GASTROENTEROL HEPATOL. (2013); 10(11): 686-90). NAFLD is a liver disease characterized by a spectrum of clinical and pathological severity ranging from simple steatosis to nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and liver failure (Bessone F, et al., CELL MOL. LIFE SCI. (2019); 76(1): 99-128). NAFLD is characterized by the presence of fat in the liver in the absence of significant alcohol use and other causes of fat accumulation in the liver such as medications, starvation, and viral disease (Chalasani, N., et al., HEPATOLOGY (Baltimore, Md.), (2012); 55(6): 2005-23). Additionally, as the disease progresses, NASH patients also have an increased risk of developing extra-hepatic complications, particularly cardiovascular diseases (CVD), which are among the most common causes of death in this patient population (Patil R, et al., WORLD J. GASTROINTEST. PATHOPHYSIOL. (2017); 8(2): 51-8). The abnormalities in hepatic lipid metabolism that lead to NAFLD also drive the progression of atherogenic dyslipidemia, where elevated plasma triglycerides (TG) cholesterol and lipoprotein particles infiltrate the arterial wall and subsequently develop atherosclerotic plaques (Loomba R & Sanyal A J NAT. REV. GASTROENTEROL. HEPATOL. (2013); 10(11): 686-90). Thus, there is a significant medical need for the development of disease modifying therapeutics for NAFLD.

SUMMARY OF DISCLOSURE

The disclosure is based in part on the discovery of oligonucleotides (e.g., RNAi oligonucleotides) that reduce NR1H3 (nuclear receptor subfamily 1, group H, member 3) expression in the liver. Specifically, target sequences within NR1H3 mRNA were identified and oligonucleotides that bind to these target sequences and inhibit NR1H3 mRNA expression were generated. As demonstrated herein, the oligonucleotides inhibited murine, monkey and/or human NR1H3 expression in the liver. Without being bound by theory, the oligonucleotides described herein are useful for treating a disease, disorder or condition associated with NR1H3 expression (e.g., non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus).

In an aspect, the invention provides an RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length. In an aspect, the invention provides an RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1125-1511, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

In some embodiments, the RNAi oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is selected from SEQ ID NOs: 786, 787, 1537 and 813, and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, the RNAi oligonucleotide comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is selected from SEQ ID NOs: 1509, 1510 1409, and 1511 and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments of the RNAi oligonucleotide: (i) the sense strand is 15 to 50 or 18 to 36 nucleotides in length, optionally 36 nucleotides in length; optionally (ii) the antisense strand is 15 to 30 nucleotides in length, optionally 22 nucleotides in length; and optionally (iii) the duplex region is at least 19 nucleotides or at least 20 nucleotides in length.

In some embodiments of the RNAi oligonucleotide, the region of complementarity is at least 19 contiguous nucleotides in length, optionally at least 20 contiguous nucleotides in length, optionally 20 contiguous nucleotides, and optionally wherein the region of complementarity is fully complementary to the mRNA target sequence at nucleotide positions 2-8 of the antisense strand or positions 2-11 of the antisense strand, nucleotide numbering 5′ to 3′.

In some embodiments of the RNAi oligonucleotide: the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein (i) S1 is complementary to S2, optionally wherein S1 and S2 are each 1-10 nucleotides in length and have the same length, optionally wherein S1 and S2 are each 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length, further optionally wherein S1 and S2 are 6 nucleotides in length; and (ii) L forms a loop between S1 and S2 of 3-5 nucleotides in length, optionally wherein L is a triloop or a tetraloop, optionally wherein the tetraloop comprises the sequence 5′-GAAA-3′, optionally wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121). In some embodiments of the RNAi oligonucleotide comprises a nicked tetraloop structure or comprises a nick between the 3′ terminus of the sense strand and the 5′ terminus of the antisense strand.

In some embodiments of the RNAi oligonucleotide: the antisense strand comprises an overhang sequence of one or more nucleotides in length at the 3′ terminus, optionally wherein the overhang comprises purine nucleotides, optionally wherein the overhang sequence is 2 nucleotides in length, optionally wherein the overhang is selected from AA, GG, AG, and GA, optionally wherein the overhang is GG.

In some embodiments of the RNAi oligonucleotide: (i) the oligonucleotide comprises at least one modified nucleotide, optionally wherein the modified nucleotide comprises a 2′-modification, optionally wherein: (a) the 2′-modification is a modification selected from 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid, optionally wherein the modification is selected from 2′-fluoro and 2′-O-methyl, optionally wherein all nucleotides of the oligonucleotide are modified, wherein the modification is 2′-fluoro and 2′-O-methyl; (b) about 10-15%, 10%, 11%, 12%, 13%, 14%, or 15% of the nucleotides of the sense strand comprise a 2′-fluoro modification; (c) about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the antisense strand comprise a 2′-fluoro modification; (d) about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the oligonucleotide comprise a 2′-fluoro modification; (e) the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein positions 8-11 comprise a 2′-fluoro modification; (f) the antisense strand comprises 22 nucleotides with positions 1-22 from 5′ to 3′, and wherein positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2′-fluoro modification; and/or (g) the remaining nucleotides comprise a 2′-O-methyl modification, and/or (ii) the oligonucleotide comprises at least one modified internucleotide linkage, optionally wherein the at least one modified internucleotide linkage is a phosphorothioate linkage, optionally wherein: (a) the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5′ to 3′; and/or (b) the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5′ to 3′, and/or (iii) the antisense strand comprises a phosphorylated nucleotide at the 5′ terminus, wherein the phosphorylated nucleotide is selected from uridine and adenosine, optionally wherein the phosphorylated nucleotide is uridine, and/or (iv) the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, optionally wherein the phosphate analog is oxymethylphosphonate, vinylphosphonate or malonylphosphonate, optionally wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy, and/or (v) at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands, optionally wherein: (a) each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide or lipid; (b) the stem loop comprises one or more targeting ligands conjugated to one or more nucleotides of the stem loop; (c) the one or more targeting ligands is conjugated to one or more nucleotides of the loop, optionally wherein the loop comprises 4 nucleotides numbered 1-4 from 5′ to 3′, wherein nucleotides at positions 2, 3, and 4 each comprise one or more targeting ligands, wherein the targeting ligands are the same or different; (d) each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety, optionally wherein the GalNAc moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety; and/or (e) up to 4 nucleotides of L of the stem-loop are each conjugated to a monovalent GalNAc moiety.

In some embodiments of the RNAi oligonucleotide, the targeting ligand comprises at least one GalNAc moiety and targets human liver cells (e.g., human hepatocytes).

In some embodiments of the RNAi oligonucleotide: (i) the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 769-856, SEQ ID NOs: 1519-1552, SEQ ID NOs: 1409, 1509-1511, or SEQ ID NOs: 945-1032, optionally a nucleotide sequence selected from SEQ ID NOs: SEQ ID NOs: 786, 787, 813, and 1537; and optionally (ii) the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 857-944 or SEQ ID NOs: 1033-1120, optionally a nucleotide sequence selected from SEQ ID NOs: 874, 875, 901, and 929.

In some embodiments of the RNAi oligonucleotide: the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of: (a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively.

In some embodiments of the RNAi oligonucleotide: the sense and antisense strands comprise nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 945 and 1033, respectively; (b) SEQ ID NOs: 946 and 1034, respectively; (c) SEQ ID NOs: 947 and 1035, respectively; (d) SEQ ID NOs: 948 and 1036, respectively; (e) SEQ ID NOs: 949 and 1037, respectively; (f) SEQ ID NOs: 950 and 1038, respectively; (g) SEQ ID NOs: 951 and 1039, respectively; (h) SEQ ID NOs: 952 and 1040, respectively; (i) SEQ ID NOs: 953 and 1041, respectively; (j) SEQ ID NOs: 954 and 1042, respectively; (k) SEQ ID NOs: 955 and 1043, respectively; (l) SEQ ID NOs: 956 and 1044 respectively; (m) SEQ ID NOs: 957 and 1045, respectively; (n) SEQ ID NOs: 958 and 1046, respectively; (o) SEQ ID NOs: 959 and 1047, respectively; (p) SEQ ID NOs: 960 and 1048, respectively; (q) SEQ ID NOs: 961 and 1049, respectively; (r) SEQ ID NOs: 962 and 1050, respectively; (s) SEQ ID NOs: 963 and 1051, respectively; (t) SEQ ID NOs: 964 and 1052, respectively; (u) SEQ ID NOs: 965 and 1053, respectively; (v) SEQ ID NOs: 966 and 1054, respectively; (w) SEQ ID NOs: 967 and 1055, respectively; (x) SEQ ID NOs: 968 and 1056, respectively; (y) SEQ ID NOs: 969 and 1057, respectively; (z) SEQ ID NOs: 970 and 1058, respectively; (aa) SEQ ID NOs: 971 and 1059, respectively; (bb) SEQ ID NOs: 972 and 1060, respectively; (cc) SEQ ID NOs: 973 and 1061, respectively; (dd) SEQ ID NOs: 974 and 1062, respectively; (ee) SEQ ID NOs: 975 and 1063, respectively; (ff) SEQ ID NOs: 976 and 1064, respectively; (gg) SEQ ID NOs: 977 and 1065, respectively; (hh) SEQ ID NOs: 978 and 1066, respectively; (ii) SEQ ID NOs: 979 and 1067, respectively; (jj) SEQ ID NOs: 980 and 1068, respectively; (kk) SEQ ID NOs: 981 and 1069, respectively; (ll) SEQ ID NOs: 982 and 1070, respectively; (mm) SEQ ID NOs: 983 and 1071, respectively; (nn) SEQ ID NOs: 984 and 1072, respectively; (oo) SEQ ID NOs: 985 and 1073, respectively; (pp) SEQ ID NOs: 986 and 1074, respectively; (qq) SEQ ID NOs: 987 and 1075, respectively; (rr) SEQ ID NOs: 988 and 1076, respectively; (ss) SEQ ID NOs: 989 and 1077, respectively; (tt) SEQ ID NOs: 990 and 1078, respectively; (uu) SEQ ID NOs: 991 and 1079, respectively; (vv) SEQ ID NOs: 992 and 1080, respectively; (ww) SEQ ID NOs: 993 and 1081, respectively; (xx) SEQ ID NOs: 994 and 1082, respectively; (yy) SEQ ID NOs: 995 and 1083, respectively; (zz) SEQ ID NOs: 996 and 1084, respectively; (aaa) SEQ ID NOs: 997 and 1085, respectively; (bbb) SEQ ID NOs: 998 and 1086, respectively; (ccc) SEQ ID NOs: 999 and 1087, respectively; (ddd) SEQ ID NOs: 1000 and 1088, respectively; (eee) SEQ ID NOs: 1001 and 1089, respectively; (fff) SEQ ID NOs: 1002 and 1090, respectively; (ggg) SEQ ID NOs: 1003 and 1091, respectively; (hhh) SEQ ID NOs: 1004 and 1092 respectively; (iii) SEQ ID NOs: 1005 and 1093 respectively; (jjj) SEQ ID NOs: 1006 and 1094, respectively; (kkk) SEQ ID NOs: 1007 and 1095, respectively; (lll) SEQ ID NOs: 1008 and 1096, respectively; (mmm) SEQ ID NOs: 1009 and 1097, respectively; (nnn) SEQ ID NOs: 1010 and 1098, respectively; (ooo) SEQ ID NOs: 1011 and 1099, respectively; (ppp) SEQ ID NOs: 1012 and 1100, respectively; (qqq) SEQ ID NOs: 1013 and 1101, respectively; (rrr) SEQ ID NOs: 1014 and 1102 respectively; (sss) SEQ ID NOs: 1015 and 1103, respectively; (ttt) SEQ ID NOs: 1016 and 1104, respectively; (uuu) SEQ ID NOs: 1017 and 1105, respectively; (vvv) SEQ ID NOs: 1018 and 1106, respectively; (www) SEQ ID NOs: 1019 and 1107, respectively; (xxx) SEQ ID NOs: 1020 and 1108, respectively; (yyy) SEQ ID NOs: 1021 and 1109, respectively; (zzz) SEQ ID NOs: 1022 and 1110, respectively; (aaaa) SEQ ID NOs: 1023 and 1111, respectively; (bbbb) SEQ ID NOs: 1024 and 1112, respectively; (cccc) SEQ ID NOs: 1025 and 1113, respectively; (dddd) SEQ ID NOs: 1026 and 1114, respectively; (eeee) SEQ ID NOs: 1027 and 1115, respectively; (ffff) SEQ ID NOs: 1028 and 1116, respectively; (gggg) SEQ ID NOs: 1029 and 1117, respectively; (hhhh) SEQ ID NOs: 1030 and 1118, respectively; (iiii) SEQ ID NOs: 1031 and 1119, respectively; and, (jjjj) SEQ ID NOs: 1032 and 1120, respectively. In some embodiments of the RNAi oligonucleotide: (i) the sense strand comprises the sequence and all of the modifications of 5′-mCs-mU-mC-mA-mA-mG-mG-fA-fU-fU-fU-mC-mA-mG-mU-mU-mA-mU-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 963), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fAs-fU-fA-mA-fC-mU-mG-fA-mA-mA-mU-fC-mC-mU-mU-mG-mA-mGs-mGs-mG-3′ (SEQ ID NO: 1051), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=Chem. formula 5

(ii) the sense strand comprises the sequence and all of the modifications of 5′-mUs-mC-mA-mA-mG-mG-mA-fU-fU-fU-fC-mA-mG-mU-mU-mA-mU-mA-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 964), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fUs-fA-fU-mA-fA-mC-mU-fG-mA-mA-mA-fU-mC-mC-mU-mU-mG-mAs-mGs-mG-3′ (SEQ ID NO: 1052), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=Chem. formula 5

(iii) the sense strand comprises the sequence and all of the modifications of 5′-mAs-mG-mC-mA-mG-mC-mG-fU-fC-fC-fA-mC-mU-mC-mA-mG-mA-mG-mC-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1006), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fGs-fCs-fU-fC-mU-fG-mA-mG-fU-mG-mG-mA-fC-mG-mC-mU-mG-mC-mUs-mGs-mG-3′ (SEQ ID NO: 1094), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=Chem. formula 5

(iv) the sense strand comprises the sequence and all of the modifications of 5′-mAs-mU-mG-mU-mG-mC-mA-fC-fG-fA-fA-mU-mG-mA-mC-mU-mG-mU-mU-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1018), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fAs-fAs-fC-fA-mG-fU-mC-mA-fU-mU-mC-mG-fU-mG-mC-mA-mC-mA-mUs-mGs-mG-3′ (SEQ ID NO: 1106), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=Chem. formula 5

optionally wherein the oligonucleotide is a Dicer substrate.

In an aspect, the invention provides a pharmaceutical composition comprising the RNAi oligonucleotide according to the invention and a pharmaceutically acceptable carrier, delivery agent or excipient.

In an aspect, the invention provides a kit comprising the RNAi oligonucleotide according to the invention, an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration to a subject having a disease, disorder or condition associated with NR1H3 expression, optionally for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus

In an aspect, the invention provides the use of the RNAi oligonucleotide according to the invention, or the pharmaceutical composition according to the invention, in the manufacture of a medicament for the treatment of a disease, disorder or condition associated with NR1H3 expression, optionally for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus, optionally for use in in combination with a second composition or therapeutic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A provides a drawing of an oligonucleotide comprising a nicked tetraloop structure.

FIG. 1B provides a graph depicting the percent (%) remaining human NR1H3 mRNA in liver of mice exogenously expressing human NR1H3 (hydrodynamic injection model) after treatment with GalNAc-conjugated NR1H3 oligonucleotides. Three days post-dose mice were hydrodynamically injected (HDI) with the human NR1H3 mRNA construct. 18 hours later, livers were collected and human and mouse NR1H3 mRNA levels were measured. Exons indicate the location on the mRNA where the construct targets. Constructs tested in FIG. 1B were selected from the screen described in Example 2. White arrows indicate potential constructs for non-human primate (NHP) studies.

FIG. 2 provides graphs depicting the percentage (%) of remaining human or mouse NR1H3 mRNA in liver of mice exogenously expressing human NR1H3 (hydrodynamic injection model) after treatment with GalNAc-conjugated NR1H3 oligonucleotides designed based on sequences identified using the algorithm described in Example 2. Mice were dosed subcutaneously with 2 mg/kg of the indicated NR1H3-GalNAc construct. Three days post-dose mice were hydrodynamically injected (HDI) with the human NR1H3 mRNA construct. 18 hours later, livers were collected and human and mouse NR1H3 mRNA levels were measured. Exons indicate the location on the mRNA where the construct targets. Benchmark constructs (NR1H3-769 and NR1H3-1469) were selected from prior sequence screening conducted at Dicerna.

FIG. 3 provides a graph depicting the percent (%) remaining human NR1H3 mRNA in liver of mice exogenously expressing human NR1H3 (HDI model) after treatment with GalNAc-conjugated NR1H3 oligonucleotides. Constructs tested in FIG. 3 are a repeat assay validating the constructs tested in FIG. 2. White arrows indicate potential constructs for non-human primate studies.

FIG. 4 provides a graph depicting the percent (%) remaining human NR1H3 mRNA in liver of mice exogenously expressing human NR1H3 (HDI model) after treatment with GalNAc-conjugated NR1H3 oligonucleotides. Constructs tested in FIG. 1B and FIG. 2 were validated and repeated in two assays (experiment 1 and experiment 2) using the same methods. White arrows indicate potential constructs for non-human primate studies.

FIG. 5 provides a schematic depicting the dosing scheme and specimen collection for treatment of non-human primates with GalNAc-conjugated NR1H3 oligonucleotides. 1 mg/kg or 4 mg/kg are dosed once every 4 weeks for four months (Q4W×4). Timing for liver biopsies and blood collection is shown.

DETAILED DESCRIPTION

The liver X receptors α (LXRα; encoded by the NR1H3 gene) and β (LXRβ; encoded by NR1H2 gene) are nuclear receptors that function in the regulation of lipid and cholesterol homeostasis, as well as inflammation (Venkateswaran, A., et al., PROC. NATL. ACAD. SCI. U.S.A, (2000); 97: 12097-102). LXRα is highly expressed in lipid metabolism-related organs such as the liver, small intestine, kidney, spleen, adrenal gland, and adipose tissue, whereas LXRβ expression is distributed ubiquitously. The hypothesis of specific inhibition of LXRα in the hepatocytes to treat NASH-related dyslipidemia is supported by several clinical and pre-clinical observations. Activation of LXRα increases plasma and hepatic TG and plasma LDLc, as was demonstrated in human subjects treated with LXR agonist in a dose-dependent manner (Kirchgessner, T. G., et al., CELL METAB, (2016); 24(2): 223-33). Consistent with this observation, hepatic deletion of LXRα in mice lowers liver fat and reduces plasma triglycerides. (J. CLIN. INVEST. (2012); 122(5): 1688-99.

In addition, hepatic expression of LXRα is significantly upregulated in liver biopsies from NAFLD and NASH patients (Ahn, S. B., et al. DIG. DIS. SCI. (2014); 59: 2975-82). However, avoiding inhibition of LXRα in macrophages is desirable as LXRα activation increases reverse cholesterol transport (RCT) which prevents atherosclerosis (CURR. OPIN. INVESTIG. DRUGS. (2003); 4(9): 1053-8). Taken together, and without being bound by theory, antagonism/inhibition of LXRα specifically in hepatocytes (e.g., via NR1H3-targeted RNAi oligonucleotides) decreases de novo lipogenesis with concomitant preservation of LXRα function in macrophages and stellate cells for their positive roles in preventing inflammation and fibrosis respectively, thus representing a promising approach for treatment of NAFLD and/or NASH. (Higuchi, N., et al., HEPATOL. RES. (2008); 38: 1122-29) (Repa, J. J.; and, Mangelsdorf, D. J. ANNU. REV. CELL DEV. BIOL. (2000); 16: 459-81). This approach may be best managed by a specific and targeted reduction of the NR1H3 expression in the liver while other organs, tissues or cells expressing NR1H3 are left essentially alone. In this sense the current invention may provide an improved modality of treatment given its specific targeting of mRNA production in the liver.

According to some aspects, the disclosure provides oligonucleotides (e.g., RNAi oligonucleotides) that reduce NR1H3 expression in the liver. In some embodiments, the oligonucleotides provided herein are designed to treat diseases associated with NR1H3 expression in the liver, e.g., non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH). In some respects, the disclosure provides methods of treating a disease associated with NR1H3 expression by reducing NR1H3 expression in cells (e.g., cells of the liver) or in organs (e.g., liver).

Oligonucleotide Inhibitors of NR1H3 Expression NR1H3 Target Sequences

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) is targeted to a target sequence comprising a NR1H3 mRNA. In some embodiments, an oligonucleotide described herein is targeted to a target sequence within a NR1H3 mRNA sequence. In some embodiments, the oligonucleotide described herein corresponds to a target sequence within a NR1H3 mRNA sequence. In some embodiments, the oligonucleotide, or a portion, fragment, or strand thereof (e.g., an antisense strand or a guide strand of a double-stranded (ds) RNAi oligonucleotide) binds or anneals to a target sequence comprising NR1H3 mRNA, thereby inhibiting NR1H3 expression.

In some embodiments, the oligonucleotide is targeted to a NR1H3 target sequence for the purpose of inhibiting NR1H3 expression in vivo. In some embodiments, the amount or extent of inhibition of NR1H3 expression by an oligonucleotide targeted to a NR1H3 target sequence correlates with the potency of the oligonucleotide. In some embodiments, the amount or extent of inhibition of NR1H3 expression by an oligonucleotide targeted to a NR1H3 target sequence correlates with the amount or extent of therapeutic benefit in a subject or patient having a disease, disorder or condition associated with NR1H3 expression treated with the oligonucleotide.

Through examination of the nucleotide sequence of mRNAs encoding NR1H3, including mRNAs of multiple different species (e.g., human, cynomolgus monkey, mouse, and rat; see, e.g., Example 2) and as a result of in vitro and in vivo testing (see, e.g., Examples 2-5), it has been discovered that certain nucleotide sequences of NR1H3 mRNA are more amenable than others to oligonucleotide-based inhibition and are thus useful as target sequences for the oligonucleotides herein. In some embodiments, a sense strand of an oligonucleotide (e.g., an RNAi oligonucleotide) described herein comprises a NR1H3 target sequence. In some embodiments, a portion or region of the sense strand of an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a NR1H3 target sequence. In some embodiments, a NR1H3 target sequence comprises, or consists of, a sequence of any one of SEQ ID NOs: 1-384. In some embodiments, a NR1H3 target sequence can consist of one of the sequences set forth in SEQ ID NO: 92, 285, and/or 354.

NR1H3 Targeting Sequences

In some embodiments, the oligonucleotides herein (e.g., RNAi oligonucleotides) have regions of complementarity to NR1H3 mRNA (e.g., within a target sequence of NR1H3 mRNA) for purposes of targeting the NR1H3 mRNA in cells and inhibiting and/or reducing NR1H3 expression. In some embodiments, the oligonucleotides herein comprise a NR1H3 targeting sequence (e.g., an antisense strand or a guide strand of a dsRNAi oligonucleotide) having a region of complementarity that binds or anneals to a NR1H3 target sequence by complementary (Watson-Crick) base pairing. The targeting sequence or region of complementarity is generally of a suitable length and base content to enable binding or annealing of the oligonucleotide (or a strand thereof) to a NR1H3 mRNA for purposes of inhibiting and/or reducing NR1H3 expression. In some embodiments, the targeting sequence or region of complementarity is at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is about 12 to about 30 (e.g., 12 to 30, 12 to 22, 15 to 25, 17 to 21, 18 to 27, 19 to 27, or 15 to 30) nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 18 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 19 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 20 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 21 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 22 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 23 nucleotides in length. In some embodiments, the targeting sequence or region of complementarity is 24 nucleotides in length. In some embodiments, an oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1125-1511 and the targeting sequence or region of complementarity is 18 nucleotides in length. In some embodiments, an oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1-384, and the targeting sequence or region of complementarity is 19 nucleotides in length. In some embodiments, an oligonucleotide comprises a target sequence or region of complementarity complementary to a sequence of any one of SEQ ID NOs: 1125-1511, and the targeting sequence or region of complementarity is 19 nucleotides in length.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementarity (e.g., an antisense strand or a guide strand of a double-stranded oligonucleotide) that is fully complementary to a NR1H3 target sequence. In some embodiments, the targeting sequence or region of complementarity is partially complementary to a NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a NR1H3 target sequence.

In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a sequence of any one of SEQ ID NOs: 1-384. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to a sequence of any one of SEQ ID NOs: 1125-1511. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is fully complementary to the sequence set forth in SEQ ID NO: 1409, 1509, 1510 or 1511. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 1-384. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to a sequence of any one of SEQ ID NOs: 1125-1511. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is partially complementary to the sequence set forth in SEQ ID NO: 1409, 1509, 1510 or 1511.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a NR1H3 mRNA, wherein the contiguous sequence of nucleotides is about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12 to 20, 12 to 18, 12 to 16, 14 to 22, 16 to 20, 18 to 20, or 18 to 19 nucleotides in length). In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a NR1H3 mRNA, wherein the contiguous sequence of nucleotides is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a NR1H3 mRNA, wherein the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity that is complementary to a contiguous sequence of nucleotides comprising a NR1H3 mRNA, wherein the contiguous sequence of nucleotides is 20 nucleotides in length.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, optionally wherein the contiguous sequence of nucleotides is 19 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs:1409, 1509, 1510 or 1511, wherein the contiguous sequence of nucleotides is 19 nucleotides in length.

In some embodiments, a targeting sequence or region of complementarity of an oligonucleotide herein (e.g., an RNAi oligonucleotide) is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384. In some embodiments, a targeting sequence or region of complementarity of an oligonucleotide herein (e.g., an RNAi oligonucleotide) is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511. In some embodiments, a targeting sequence or region of complementarity of an oligonucleotide herein (e.g., an RNAi oligonucleotide) is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384 and spans the entire length of an antisense strand. In some embodiments, a targeting sequence or region of complementarity of the oligonucleotide is complementary to a contiguous sequence of nucleotides of SEQ ID NOs: 1-384 and spans a portion of the entire length of an antisense strand. In some embodiments, a targeting sequence or region of complementarity of the oligonucleotide is complementary to a contiguous sequence of nucleotides of SEQ ID NOs: 1125-1511 and spans a portion of the entire length of an antisense strand. In some embodiments, a targeting sequence or region of complementarity of the oligonucleotide is complementary to a contiguous sequence of nucleotides of SEQ ID NOs: 1125-1511 and spans a portion of the entire length of an antisense strand. In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a region of complementarity (e.g., on an antisense strand of a dsRNA) that is at least partially (e.g., fully) complementary to a contiguous stretch of nucleotides spanning nucleotides 1-19 or 1-20 of a sequence as set forth in any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a region of complementarity (e.g., on an antisense strand of a dsRNA) that is at least partially (e.g., fully) complementary to a contiguous stretch of nucleotides spanning nucleotides 1-19 or 1-20 of a sequence as set forth in any one of SEQ ID NOs: 1125-1511.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or region of complementarity having one or more base pair (bp) mismatches with the corresponding NR1H3 target sequence. In some embodiments, the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding NR1H3 target sequence provided that the ability of the targeting sequence or region of complementarity to bind or anneal to the NR1H3 mRNA under appropriate hybridization conditions and/or the ability of the oligonucleotide to inhibit NR1H3 expression is maintained. Alternatively, the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding NR1H3 target sequence provided that the ability of the targeting sequence or region of complementarity to bind or anneal to the NR1H3 mRNA under appropriate hybridization conditions and/or the ability of the oligonucleotide to inhibit NR1H3 expression is maintained. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 1 mismatch with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 2 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 3 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 4 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having 5 mismatches with the corresponding target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having more than one mismatch (e.g., 2, 3, 4, 5 or more mismatches) with the corresponding target sequence, wherein at least 2 (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5 or more mismatches in a row), or wherein the mismatches are interspersed throughout the targeting sequence or region of complementarity. In some embodiments, the oligonucleotide comprises a targeting sequence or region of complementarity having more than one mismatch (e.g., 2, 3, 4, 5 or more mismatches) with the corresponding target sequence, wherein at least 2 (e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3, 4, 5 or more mismatches in a row), or wherein at least one or more non-mismatched base pair is located between the mismatches, or a combination thereof. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs:1409, 1509, 1510 or 1511, wherein the targeting sequence or region of complementarity may have up to about 1, up to about 2, up to about 3, up to about 4, up to about 5, etc. mismatches with the corresponding NR1H3 target sequence. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1409, 1509, 1510 or 1511, wherein the targeting sequence or region of complementarity may have no more than 1, no more than 2, no more than 3, no more than 4, or no more than 5 mismatches with the corresponding NR1H3 target sequence.

Types of Oligonucleotides

A variety of oligonucleotide types and/or structures are useful for targeting NR1H3 in the methods herein including, but not limited to, RNAi oligonucleotides, antisense oligonucleotides (ASOs), miRNAs, etc. Any of the oligonucleotide types described herein or elsewhere are contemplated for use as a framework to incorporate a NR1H3 targeting sequence herein for the purposes of inhibiting NR1H3 expression.

In some embodiments, the oligonucleotides herein inhibit NR1H3 expression by engaging with RNA interference (RNAi) pathways upstream or downstream of Dicer involvement. For example, RNAi oligonucleotides have been developed with each strand having sizes of about 19-25 nucleotides with at least one 3′-overhang of 1 to 5 nucleotides (see, e.g., U.S. Pat. No. 8,372,968). Longer oligonucleotides also have been developed that are processed by Dicer to generate active RNAi products (see, e.g., U.S. Pat. No. 8,883,996). Further work produced extended dsRNAs where at least one end of at least one strand is extended beyond a duplex targeting region, including structures where one of the strands includes a thermodynamically stabilizing tetraloop structure (see, e.g., U.S. Pat. Nos. 8,513,207 and 8,927,705, as well as Intl. Patent Application Publication No. WO 2010/033225). Such structures may include single-stranded (ss) extensions (on one or both sides of the molecule) as well as double-stranded (ds) extensions.

In some embodiments, the oligonucleotides herein engage with the RNAi pathway downstream of the involvement of Dicer (e.g., Dicer cleavage). In some embodiments, the oligonucleotides described herein are Dicer substrates. In some embodiments, upon endogenous Dicer processing, double-stranded nucleic acids of 19-23 nucleotides in length capable of reducing NR1H3 expression are produced. In some embodiments, the oligonucleotide has an overhang (e.g., of 1, 2, or 3 nucleotides in length) in the 3′ end of the sense strand. In some embodiments, the oligonucleotide (e.g., siRNA) comprises a 21-nucleotide guide strand that is antisense to a target RNA and a complementary passenger strand, in which both strands anneal to form a 19-bp duplex and 2 nucleotide overhangs at either or both 3′ ends. Longer oligonucleotide designs also are available including oligonucleotides having a guide strand of 23 nucleotides and a passenger strand of 21 nucleotides, where there is a blunt end on the right side of the molecule (3′ end of passenger strand/5′ end of guide strand) and a two nucleotide 3′-guide strand overhang on the left side of the molecule (5′ end of the passenger strand/3′ end of the guide strand). In such molecules, there is a 21 bp duplex region. See, e.g., U.S. Pat. Nos. 9,012,138; 9,012,621 and 9,193,753.

In some embodiments, the oligonucleotides herein comprise sense and antisense strands that are both in the range of about 17 to 36 (e.g., 17 to 36, 20 to 25, or 21-23) nucleotides in length. In some embodiments, the oligonucleotides described herein comprise an antisense strand of 19-30 nucleotides in length and a sense strand of 19-50 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand. In some embodiments, an oligonucleotide herein comprises a sense and antisense strand that are both in the range of about 19-22 nucleotides in length. In some embodiments, the sense and antisense strands are of equal length. In some embodiments, an oligonucleotide comprises sense and antisense strands, such that there is a 3′-overhang on either the sense strand or the antisense strand, or both the sense and antisense strand. In some embodiments, for oligonucleotides that have sense and antisense strands that are both in the range of about 21-23 nucleotides in length, a 3′-overhang on the sense, antisense, or both sense and antisense strands is 1 or 2 nucleotides in length. In some embodiments, the oligonucleotide has a guide strand of 22 nucleotides and a passenger strand of 20 nucleotides, where there is a blunt end on the right side of the molecule (3′ end of passenger strand/5′ end of guide strand) and a 2 nucleotide 3′-guide strand overhang on the left side of the molecule (5′ end of the passenger strand/3′ end of the guide strand). In such molecules, there is a 20 bp duplex region.

Other oligonucleotide designs for use with the compositions and methods herein include: 16-mer siRNAs (see, e.g., NUCLEIC ACIDS IN CHEMISTRY AND BIOLOGY. Blackburn (ed.), Royal Society of Chemistry, 2006), shRNAs (e.g., having 19 bp or shorter stems; see, e.g., Moore et al. METHODS MOL. BIOL. (2010); 629: 141-158), blunt siRNAs (e.g., of 19 bps in length; see, e.g., Kraynack & Baker RNA (2006); 12: 163-176), asymmetrical siRNAs (aiRNA; see, e.g., Sun et al. NAT. BIOTECHNOL. (2008); 26: 1379-1382), asymmetric shorter-duplex siRNA (see, e.g., Chang et al. MOL. THER. (2009); 17: 725-32), fork siRNAs (see, e.g., Hohjoh FEBS LETT. (2004); 557: 193-198), ss siRNAs (Elsner NAT. BIOTECHNOL. (2012); 30: 1063), dumbbell-shaped circular siRNAs (see, e.g., Abe et al. J. AM. CHEM. SOC. (2007); 129: 15108-09), and small internally segmented interfering RNA (siRNA; see, e.g., Bramsen et al. NUCLEIC ACIDS RES. (2007); 35: 5886-97). Further non-limiting examples of an oligonucleotide structures that may be used in some embodiments to reduce or inhibit the expression of NR1H3 are microRNA (miRNA), short hairpin RNA (shRNA) and short siRNA (see, e.g., Hamilton et al. EMBO J. (2002); 21: 4671-79; see also, US Patent Application Publication No. 2009/0099115).

Still, in some embodiments, an oligonucleotide for reducing or inhibiting NR1H3 expression herein is single-stranded (ss). Such structures may include but are not limited to single-stranded RNAi molecules. Recent efforts have demonstrated the activity of ss RNAi molecules (see, e.g., Matsui et al. MOL. THER. (2016); 24: 946-55). However, in some embodiments, oligonucleotides herein are antisense oligonucleotides (ASOs). An antisense oligonucleotide is a single-stranded oligonucleotide that has a nucleobase sequence which, when written in the 5′ to 3′ direction, comprises the reverse complement of a targeted segment of a particular nucleic acid and is suitably modified (e.g., as a gapmer) so as to induce RNaseH-mediated cleavage of its target RNA in cells or (e.g., as a mixmer) so as to inhibit translation of the target mRNA in cells. ASOs for use herein may be modified in any suitable manner known in the art including, for example, as shown in U.S. Pat. No. 9,567,587 (including, e.g., length, sugar moieties of the nucleobase (pyrimidine, purine), and alterations of the heterocyclic portion of the nucleobase). Further, ASOs have been used for decades to reduce expression of specific target genes (see, e.g., Bennett et al. ANNU. REV. PHARMACOL. (2017); 57: 81-105).

In some embodiments, the antisense oligonucleotide shares a region of complementarity with NR1H3 mRNA. In some embodiments, the antisense oligonucleotide targets the human NR1H3 mRNA (Homo sapiens NR1H3, mRNA, transcript variant 5, NCBI Reference Sequence: NM_001251935.1). In some embodiments, the antisense oligonucleotide is 15-50 nucleotides in length. In some embodiments, the antisense oligonucleotide is 15-25 nucleotides in length. In some embodiments, the antisense oligonucleotide is 22 nucleotides in length. In some embodiments, the antisense oligonucleotide is complementary to any one of SEQ ID NOs: 1-384. In some embodiments, the antisense oligonucleotide is complementary to any one of SEQ ID NOs: 1125-1511. In some embodiments, the antisense oligonucleotide is at least 15 contiguous nucleotides in length. In some embodiments, the antisense oligonucleotide is at least 19 contiguous nucleotides in length. In some embodiments, the antisense oligonucleotide is at least 20 contiguous nucleotides in length. In some embodiments, the antisense oligonucleotide differs by 1, 2, or 3 nucleotides from the target sequence.

Double-Stranded Oligonucleotides

In some aspects, the disclosure provides double-stranded (ds) RNAi oligonucleotides for targeting NR1H3 mRNA and inhibiting NR1H3 expression (e.g., via the RNAi pathway) comprising a sense strand (also referred to herein as a passenger strand) and an antisense strand (also referred to herein as a guide strand). In some embodiments, the sense strand and antisense strand are separate strands and are not covalently linked. In some embodiments, the sense strand and antisense strand are covalently linked. In some embodiments, the sense strand and antisense strand form a duplex region, wherein the sense strand and antisense strand, or a portion thereof, binds with one another in a complementary fashion (e.g., by Watson-Crick base pairing).

In some embodiments, the sense strand has a first region (R1) and a second region (R2), wherein R2 comprises a first subregion (S1), a tetraloop (L) or triloop (triL), and a second subregion (S2), wherein L or triL is located between S1 and S2, and wherein S1 and S2 form a second duplex (D2). D2 may have various length. In some embodiments, D2 is about 1-6 bp in length. In some embodiments, D2 is 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, or 4-5 bp in length. In some embodiments, D2 is 1, 2, 3, 4, 5, or 6 bp in length. In some embodiments, D2 is 6 bp in length. In some embodiments, R1 of the sense strand and the antisense strand form a first duplex (D1). In some embodiments, D1 is at least about 15 (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21) nucleotides in length. In some embodiments, D1 is in the range of about 12 to 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 15 to 22, 18 to 22, 18 to 25, 18 to 27, 18 to 30, or 21 to 30 nucleotides in length). In some embodiments, D1 is at least 12 nucleotides in length (e.g., at least 12, at least 15, at least 20, at least 25, or at least 30 nucleotides in length). In some embodiments, D1 is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, D1 is 20 nucleotides in length. In some embodiments, D1 comprising sense strand and antisense strand does not span the entire length of the sense strand and/or antisense strand. In some embodiments, D1 comprising the sense strand and antisense strand spans the entire length of either the sense strand or antisense strand or both. In certain embodiments, D1 comprising the sense strand and antisense strand spans the entire length of both the sense strand and the antisense strand.

In some embodiments, an oligonucleotide provided herein comprises a sense strand having a sequence of any one of SEQ ID NOs: 1-384 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 385-768. In some embodiments, an oligonucleotide provided herein comprises a sense strand having a sequence of any one of SEQ ID NOs: 1125-1511 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 1512-1515.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 769-856 or 1519-1552 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 857-944 as is arranged in Tables 3 and 4.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively.

In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 786 and the antisense strand comprises the sequence of SEQ ID NO: 874.

In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 787 and the antisense strand comprises the sequence of SEQ ID NO: 875.

In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 1537 and the antisense strand comprises the sequence of SEQ ID NO: 929.

In some embodiments, the sense strand comprises the sequence of SEQ ID NO: 813 and the antisense strand comprises the sequence of SEQ ID NO: 901.

It should be appreciated that, in some embodiments, sequences presented in the Sequence Listing may be referred to in describing the structure of an oligonucleotide (e.g., a dsRNAi oligonucleotide) or other nucleic acid. In such embodiments, the actual oligonucleotide or other nucleic acid may have one or more alternative nucleotides (e.g., an RNA counterpart of a DNA nucleotide or a DNA counterpart of an RNA nucleotide) and/or one or more modified nucleotides and/or one or more modified internucleotide linkages and/or one or more other modification when compared with the specified sequence while retaining essentially same or similar complementary properties as the specified sequence.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a 25-nucleotide sense strand and a 27-nucleotide antisense strand that when acted upon by a Dicer enzyme results in an antisense strand that is incorporated into the mature RISC. In some embodiments, the 25-nucleotide sense strand comprises a sequence selected from SEQ ID NOs: 1-384. In some embodiments, the 27-nucleotide antisense strand comprises a sequence selected from SEQ ID NOs: 385-768. In some embodiments, the sense strand of the oligonucleotide is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides). In some embodiments, the sense strand of the oligonucleotide is longer than 25 nucleotides (e.g., 26, 27, 28, 29, or 30 nucleotides). In some embodiments, the sense strand of the oligonucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 769-856, wherein the nucleotide sequence is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides).). In some embodiments, the sense strand of the oligonucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 1519-1552, wherein the nucleotide sequence is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides). In some embodiments, the sense strand of the oligonucleotide comprises a nucleotide sequence selected from SEQ ID NOs: 769-856, wherein the nucleotide sequence is longer than 25 nucleotides (e.g., 26, 27, 28, 29 or 30 nucleotides).

In some embodiments, oligonucleotides herein (e.g., RNAi oligonucleotides) have one 5′ end that is thermodynamically less stable when compared to the other 5′ end. In some embodiments, an asymmetric oligonucleotide is provided that includes a blunt end at the 3′ end of a sense strand and a 3′-overhang at the 3′ end of an antisense strand. In some embodiments, the 3′-overhang on the antisense strand is about 1-8 nucleotides in length (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides in length). In some embodiments, the oligonucleotide has an overhang comprising two (2) nucleotides on the 3′ end of the antisense (guide) strand. However, other overhangs are possible. In some embodiments, an overhang is a 3′-overhang comprising a length of between 1 and 6 nucleotides, optionally 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, 5 to 6 nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides. However, in some embodiments, the overhang is a 5′-overhang comprising a length of between 1 and 6 nucleotides, optionally 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, 5 to 6 nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, and a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, and a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 769-856, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1519-1552, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises an antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 769-856 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1519-1552 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the oligonucleotide comprises a 5′-overhang comprising a length of between 1 and 6 nucleotides.

In some embodiments, two (2) terminal nucleotides on the 3′ end of an antisense strand are modified. In some embodiments, the two (2) terminal nucleotides on the 3′ end of the antisense strand are complementary with the target mRNA (e.g., NR1H3 mRNA). In some embodiments, the two (2) terminal nucleotides on the 3′ end of the antisense strand are not complementary with the target mRNA. In some embodiments, the two (2) terminal nucleotides on the 3′ end of the antisense strand of an oligonucleotide herein are unpaired. In some embodiments, the two (2) terminal nucleotides on the 3′ end of the antisense strand of an oligonucleotide herein comprise an unpaired GG. In some embodiments, the two (2) terminal nucleotides on the 3′ end of an antisense strand of an oligonucleotide herein are not complementary to the target mRNA. In some embodiments, two (2) terminal nucleotides on each 3′ end of an oligonucleotide are GG. In some embodiments, one or both of the two (2) terminal GG nucleotides on each 3′ end of an oligonucleotide herein is not complementary with the target mRNA. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide herein comprises an unpaired GG. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide herein comprises an unpaired GG. In some embodiments, the oligonucleotide comprises an antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide comprises an unpaired GG. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 769-856 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide comprises an unpaired GG. In some embodiments, the oligonucleotide comprises a sense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1519-1552 and antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 857-944, wherein the two (2) terminal nucleotides on the 3′ end of the antisense strand of the oligonucleotide comprises an unpaired GG.

In some embodiments, there is one or more (e.g., 1, 2, 3, 4, or 5) mismatch(s) between a sense and antisense strand comprising an oligonucleotide herein (e.g., an RNAi oligonucleotide). If there is more than one mismatch between a sense and antisense strand, they may be positioned consecutively (e.g., 2, 3 or more in a row), or interspersed throughout the region of complementarity. In some embodiments, the 3′ end of the sense strand comprises one or more mismatches. In some embodiments, two (2) mismatches are incorporated at the 3′ end of the sense strand. In some embodiments, base mismatches, or destabilization of segments at the 3′ end of the sense strand of an oligonucleotide herein improves or increases the potency of the oligonucleotide. In some embodiments, the sense and antisense strands of an oligonucleotide herein comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein there is one or more (e.g., 1, 2, 3, 4 or 5) mismatch(s) between the sense and antisense strands.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand comprising nucleotide sequences selected from:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively,

wherein there is one or more (e.g., 1, 2, 3, 4, or 5) mismatch(s) between the sense and antisense strands.

Antisense Strands

In some embodiments, an antisense strand of an oligonucleotide herein (e.g., an RNAi oligonucleotide) is referred to as a “guide strand”. For example, an antisense strand that engages with RNA-induced silencing complex (RISC) and binds to an Argonaute protein such as Ago2, or engages with or binds to one or more similar factors, and directs silencing of a target gene, as the antisense strand is referred to as a guide strand. In some embodiments, a sense strand comprising a region of complementary to a guide strand is referred to herein as a “passenger strand.” In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises an antisense strand of up to about 50 nucleotides in length (e.g., up to 50, up to 40, up to 35, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, or up to 12 nucleotides in length).

In some embodiments, an oligonucleotide comprises an antisense strand of at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 22, at least 25, at least 27, at least 30, at least 35, or at least 38 nucleotides in length). In some embodiments, an oligonucleotide comprises an antisense strand in a range of about 12 to about 40 (e.g., 12 to 40, 12 to 36, 12 to 32, 12 to 28, 15 to 40, 15 to 36, 15 to 32, 15 to 28, 17 to 22, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to 40, or 32 to 40) nucleotides in length. In some embodiments, an oligonucleotide comprises antisense strand of 15 to 30 nucleotides in length. In some embodiments, an antisense strand of any one of the oligonucleotides disclosed herein is of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides in length. In some embodiments, an oligonucleotide comprises an antisense strand of 22 nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) for targeting NR1H3 comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 385-768. In some embodiments, an oligonucleotide herein comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 385-768. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 857-944. In some embodiments, an oligonucleotide herein comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 857-944. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 comprises an antisense strand comprising or consisting of a sequence as set forth in any one of SEQ ID NOs: 874, 875, 929, and 901. In some embodiments, an oligonucleotide herein comprises an antisense strand comprising at least about 12 (e.g., at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22 or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 874, 875, 929, and 901.

In some embodiments, an oligonucleotide herein comprises an antisense strand comprising a nucleotide sequence selected from SEQ ID NOs: 1512-1515.

Sense Strands

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1125-1511. In some embodiments, an oligonucleotide herein has a sense strand comprised of at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in in any one of SEQ ID NOs: 1-384. In some embodiments, an oligonucleotide herein has a sense strand comprised of at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22 or at least 23) contiguous nucleotides of a sequence as set forth in in any one of SEQ ID NOs: 1125-1511. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 769-856. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1519-1552. In some embodiments, an oligonucleotide herein has a sense strand comprised of least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 769-856. In some embodiments, an oligonucleotide herein has a sense strand comprised of least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1519-1552. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 786, 787, 1537, and 813. In some embodiments, an oligonucleotide herein has a sense strand that comprise at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 786, 787, 1537, and 813. In some embodiments, an oligonucleotide disclosed herein for targeting NR1H3 mRNA and inhibiting NR1H3 expression comprises a sense strand sequence as set forth in any one of SEQ ID NOs: 1409, 1509, 1510 and 1511. In some embodiments, an oligonucleotide herein has a sense strand that comprise at least about 12 (e.g., at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22 or at least 23) contiguous nucleotides of a sequence as set forth in any one of SEQ ID NOs: 1409, 1509, 1510 and 1511.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand (or passenger strand) of up to about 50 nucleotides in length (e.g., up to 50, up to 40, up to 36, up to 30, up to 27, up to 25, up to 21, up to 19, up to 17, or up to 12 nucleotides in length). In some embodiments, an oligonucleotide herein comprises a sense strand of at least about 12 nucleotides in length (e.g., at least 12, at least 15, at least 19, at least 21, at least 25, at least 27, at least 30, at least 36, or at least 38 nucleotides in length). In some embodiments, an oligonucleotide herein comprises a sense strand in a range of about 12 to about 50 (e.g., 12 to 50, 12 to 40, 12 to 36, 12 to 32, 12 to 28, 15 to 40, 15 to 36, 15 to 32, 15 to 28, 17 to 21, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to 40, or 32 to 40) nucleotides in length. In some embodiments, an oligonucleotide herein comprises a sense strand of 15 to 50 nucleotides in length. In some embodiments, an oligonucleotide herein comprises a sense strand of 18 to 36 nucleotides in length. In some embodiments, an oligonucleotide herein comprises a sense strand of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length. In some embodiments, an oligonucleotide herein comprises a sense strand of 36 nucleotides in length.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand comprising a stem-loop structure at the 3′ end of the sense strand. In some embodiments, the stem-loop is formed by intrastrand base pairing. In some embodiments, a sense strand comprises a stem-loop structure at its 5′ end. In some embodiments, the stem of the stem-loop comprises a duplex of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 2 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 3 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 4 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 5 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 6 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 7 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 8 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 9 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 10 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 11 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 12 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 13 nucleotides in length. In some embodiments, the stem of the stem-loop comprises a duplex of 14 nucleotides in length.

In some embodiments, a stem-loop provides the oligonucleotide protection against degradation (e.g., enzymatic degradation), facilitates or improves targeting and/or delivery to a target cell, tissue, or organ (e.g., the liver), or both. For example, in some embodiments, the loop of a stem-loop is comprised of nucleotides comprising one or more modifications that facilitate, improve, or increase targeting to a target mRNA (e.g., a NR1H3 mRNA), inhibition of target gene expression (e.g., NR1H3 expression), and/or delivery, uptake, and/or penetrance into a target cell, tissue, or organ (e.g., the liver), or a combination thereof. In some embodiments, the stem-loop itself or modification(s) to the stem-loop do not affect or do not substantially affect the inherent gene expression inhibition activity of the oligonucleotide, but facilitates, improves, or increases stability (e.g., provides protection against degradation) and/or delivery, uptake, and/or penetrance of the oligonucleotide to a target cell, tissue, or organ (e.g., the liver). In certain embodiments, an oligonucleotide herein comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop of linked nucleotides between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides in length). In some embodiments, the loop (L) is 3 nucleotides in length. In some embodiments, the loop (L) is 4 nucleotides in length. In some embodiments, the loop (L) is 5 nucleotides in length. In some embodiments, the loop (L) is 6 nucleotides in length. In some embodiments, the loop (L) is 7 nucleotides in length. In some embodiments, the loop (L) is 8 nucleotides in length. In some embodiments, the loop (L) is 9 nucleotides in length. In some embodiments, the loop (L) is 10 nucleotides in length.

In some embodiments, the tetraloop comprises the sequence 5′-GAAA-3′. In some embodiments, the stem loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121).

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of up to about 10 nucleotides in length (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of 4 nucleotides in length.

In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of 4 nucleotides in length. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511, and the oligonucleotide comprises a sense strand comprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a single-stranded loop between S1 and S2 of 4 nucleotides in length.

In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described herein is a triloop. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384 and a triloop. In some embodiments, the triloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, ligands (e.g., delivery ligands), and combinations thereof. In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described herein is a triloop. In some embodiments, the oligonucleotide comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511 and a triloop. In some embodiments, the triloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, ligands (e.g., delivery ligands), and combinations thereof.

In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described above is a tetraloop. In some embodiments, an oligonucleotide herein comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1-384 and a tetraloop. In some embodiments, the tetraloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, ligands (e.g., delivery ligands), and combinations thereof. In some embodiments, a loop (L) of a stem-loop having the structure S1-L-S2 as described above is a tetraloop. In some embodiments, an oligonucleotide herein comprises a targeting sequence or a region of complementary that is complementary to a contiguous sequence of nucleotides of any one of SEQ ID NOs: 1125-1511 and a tetraloop. In some embodiments, the tetraloop comprises ribonucleotides, deoxyribonucleotides, modified nucleotides, ligands (e.g., delivery ligands), and combinations thereof.

Duplex Length

In some embodiments, a duplex formed between a sense and antisense strand is at least 12 (e.g., at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21) nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is in the range of 12-30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length). In some embodiments, a duplex formed between a sense and antisense strand is 12, 13, 14, 15, 16, 17, 18, 19, 29, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 12 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 13 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 14 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 15 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 16 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 17 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 18 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 19 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 20 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 21 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 22 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 23 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 24 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 25 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 26 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 27 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 28 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 29 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand is 30 nucleotides in length. In some embodiments, a duplex formed between a sense and antisense strand does not span the entire length of the sense strand and/or antisense strand. In some embodiments, a duplex between a sense and antisense strand spans the entire length of either the sense or antisense strands. In some embodiments, a duplex between a sense and antisense strand spans the entire length of both the sense strand and the antisense strand. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein a duplex formed between a sense and antisense strand is in the range of 12-30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length)

In some embodiments, a duplex between a sense and antisense strand spans the entire length of both the sense strand and the antisense strand. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively, wherein a duplex formed between a sense and antisense strand is in the range of 12-30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12 to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to 30, or 21 to 30 nucleotides in length)

Oligonucleotide Termini

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the termini of either or both strands comprise a blunt end. In some embodiments, an oligonucleotide herein comprises sense and antisense strands that are separate strands which form an asymmetric duplex region having an overhang at the 3′ terminus of the antisense strand. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the termini of either or both strands comprise an overhang comprising one or more nucleotides. In some embodiments, the one or more nucleotides comprising the overhang are unpaired nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 3′ termini of the sense strand and the 5′ termini of the antisense strand comprise a blunt end. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 5′ termini of the sense strand and the 3′ termini of the antisense strand comprise a blunt end.

In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 3′ terminus of either or both strands comprise a 3′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the sense strand comprises a 3′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 3′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein both the sense strand and the antisense strand comprises a 3′-overhang comprising one or more nucleotides.

In some embodiments, the 3′-overhang is about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length). In some embodiments, the 3′-overhang is about one (1) to nineteen (19), one (1) to eighteen (18), one (1) to seventeen (17), one (1) to sixteen (16), one (1) to fifteen (15), one (1) to fourteen (14), one (1) to thirteen (13), one (1) to twelve (12), one (1) to eleven (11), one (1) to ten (10), one (1) to nine (9), one (1) to eight (8), one (1) to seven (7), one (1) to six (6), one (1) to five (5), one (1) to four (4), one (1) to three (3), or about one (1) to two (2) nucleotides in length. In some embodiments, the 3′-overhang is (1) nucleotide in length. In some embodiments, the 3′-overhang is two (2) nucleotides in length. In some embodiments, the 3′-overhang is three (3) nucleotides in length. In some embodiments, the 3′-overhang is four (4) nucleotides in length. In some embodiments, the 3′-overhang is five (5) nucleotides in length. In some embodiments, the 3′-overhang is six (6) nucleotides in length. In some embodiments, the 3′-overhang is seven (7) nucleotides in length. In some embodiments, the 3′-overhang is eight (8) nucleotides in length. In some embodiments, the 3′-overhang is nine (9) nucleotides in length. In some embodiments, the 3′-overhang is ten (10) nucleotides in length. In some embodiments, the 3′-overhang is eleven (11) nucleotides in length. In some embodiments, the 3′-overhang is twelve (12) nucleotides in length. In some embodiments, the 3′-overhang is thirteen (13) nucleotides in length. In some embodiments, the 3′-overhang is fourteen (14) nucleotides in length. In some embodiments, the 3′-overhang is fifteen (15) nucleotides in length. In some embodiments, the 3′-overhang is sixteen (16) nucleotides in length. In some embodiments, the 3′-overhang is seventeen (17) nucleotides in length. In some embodiments, the 3′-overhang is eighteen (18) nucleotides in length. In some embodiments, the 3′-overhang is nineteen (19) nucleotides in length. In some embodiments, the 3′-overhang is twenty (20) nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 3′-overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, and wherein the antisense strand comprises a 3′-overhang about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′-overhang is two (2) nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 3′-overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively, and wherein the antisense strand comprises a 3′-overhang about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′-overhang is two (2) nucleotides in length.

In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the 5′ terminus of either or both strands comprise a 5′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the sense strand comprises a 5′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′-overhang comprising one or more nucleotides. In some embodiments, an oligonucleotide herein comprises a sense strand and an antisense strand, wherein both the sense strand and the antisense strand comprises a 5′-overhang comprising one or more nucleotides.

In some embodiments, the 5′-overhang is about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length). In some embodiments, the 5′-overhang is about one (1) to nineteen (19), one (1) to eighteen (18), one (1) to seventeen (17), one (1) to sixteen (16), one (1) to fifteen (15), one (1) to fourteen (14), one (1) to thirteen (13), one (1) to twelve (12), one (1) to eleven (11), one (1) to ten (10), one (1) to nine (9), one (1) to eight (8), one (1) to seven (7), one (1) to six (6), one (1) to five (5), one (1) to four (4), one (1) to three (3), or about one (1) to two (2) nucleotides in length. In some embodiments, the 5′-overhang is (1) nucleotide in length. In some embodiments, the 5′-overhang is two (2) nucleotides in length. In some embodiments, the 5′-overhang is three (3) nucleotides in length. In some embodiments, the 5′-overhang is four (4) nucleotides in length. In some embodiments, the 5′-overhang is five (5) nucleotides in length. In some embodiments, the 5′-overhang is six (6) nucleotides in length. In some embodiments, the 5′-overhang is seven (7) nucleotides in length. In some embodiments, the 5′-overhang is eight (8) nucleotides in length. In some embodiments, the 5′-overhang is nine (9) nucleotides in length. In some embodiments, the 5′-overhang is ten (10) nucleotides in length. In some embodiments, the 5′-overhang is eleven (11) nucleotides in length. In some embodiments, the 5′-overhang is twelve (12) nucleotides in length. In some embodiments, the 5′-overhang is thirteen (13) nucleotides in length. In some embodiments, the 5′-overhang is fourteen (14) nucleotides in length. In some embodiments, the 5′-overhang is fifteen (15) nucleotides in length. In some embodiments, the 5′-overhang is sixteen (16) nucleotides in length. In some embodiments, the 5′-overhang is seventeen (17) nucleotides in length. In some embodiments, the 5′-overhang is eighteen (18) nucleotides in length. In some embodiments, the 5′-overhang is nineteen (19) nucleotides in length. In some embodiments, the 5′-overhang is twenty (20) nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′-overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, and wherein the antisense strand comprises a 3′-overhang about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 3′-overhang is two (2) nucleotides in length.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′-overhang, wherein the sense and antisense strands of the oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively, and wherein the antisense strand comprises a 5′-overhang about one (1) to twenty (20) nucleotides in length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 nucleotides in length), optionally wherein the 5′-overhang is two (2) nucleotides in length.

In some embodiments, one or more (e.g., 2, 3, 4, 5, or more) nucleotides comprising the 3′ terminus or 5′ terminus of a sense and/or antisense strand are modified. For example, in some embodiments, one or two terminal nucleotides of the 3′ terminus of the antisense strand are modified. In some embodiments, the last nucleotide at the 3′ terminus of an antisense strand is modified, e.g., comprises 2′ modification, e.g., a 2′-O-methoxyethyl. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1-7, 12-27 and 31-36 modified with 2′OMe. In some embodiments, the last one or two terminal nucleotides at the 3′ terminus of an antisense strand are complementary with the target. In some embodiments, the last one or two nucleotides at the 3′ terminus of the antisense strand are not complementary with the target.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the 3′ terminus of the sense strand comprises a stem-loop described herein (see FIG. 1A) and the 3′ terminus of the antisense strand comprises a 3′-overhang described herein. In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand that form a nicked tetraloop structure described herein (see FIG. 1A), wherein the 3′ terminus of the sense strand comprises a stem-loop, wherein the loop is a tetraloop described herein, and wherein the 3′ terminus of the antisense strand comprises a 3′-overhang described herein (see FIG. 1A). In some embodiments, the 3′-overhang is two (2) nucleotides in length. In some embodiments, the two (2) nucleotides comprising the 3′-overhang both comprise guanine (G) nucleobases. Typically, one or both of the nucleotides comprising the 3′-overhang of the antisense strand are not complementary with the target mRNA.

Oligonucleotide Modifications

In some embodiments, an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a modification. Oligonucleotides (e.g., RNAi oligonucleotides) may be modified in various ways to improve or control specificity, stability, delivery, bioavailability, resistance from nuclease degradation, immunogenicity, base-pairing properties, RNA distribution and cellular uptake and other features relevant to therapeutic or research use.

In some embodiments, the modification is a modified sugar. In some embodiments, the modification is a 5′-terminal phosphate group. In some embodiments, the modification is a modified internucleotide linkage. In some embodiments, the modification is a modified base. In some embodiments, an oligonucleotide described herein can comprise any one of the modifications described herein or any combination thereof. For example, in some embodiments, an oligonucleotide described herein comprises at least one modified sugar, a 5′-terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein the oligonucleotide comprises at least one modified sugar, a 5′-terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base.

In some embodiments, an oligonucleotide described herein comprises at least one modified sugar, a 5′-terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively, wherein the oligonucleotide comprises at least one modified sugar, a 5′-terminal phosphate group, at least one modified internucleotide linkage, and at least one modified base.

The number of modifications on an oligonucleotide (e.g., an RNAi oligonucleotide) and the position of those nucleotide modifications may influence the properties of an oligonucleotide. For example, oligonucleotides may be delivered in vivo by conjugating them to or encompassing them in a lipid nanoparticle (LNP) or similar carrier. However, when an oligonucleotide is not protected by an LNP or similar carrier, it may be advantageous for at least some of the nucleotides to be modified. Accordingly, in some embodiments, all or substantially all the nucleotides of an oligonucleotide are modified. In some embodiments, more than half of the nucleotides are modified. In some embodiments, less than half of the nucleotides are modified. In some embodiments, the sugar moiety of all nucleotides comprising the oligonucleotide is modified at the 2′ position. The modifications may be reversible or irreversible. In some embodiments, an oligonucleotide as disclosed herein has a number and type of modified nucleotides sufficient to cause the desired characteristics (e.g., protection from enzymatic degradation, capacity to target a desired cell after in vivo administration, and/or thermodynamic stability).

Sugar Modifications

In some embodiments, an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a modified sugar. In some embodiments, a modified sugar (also referred herein to a sugar analog) includes a modified deoxyribose or ribose moiety in which, for example, one or more modifications occur at the 2′, 3′, 4′ and/or 5′ carbon position of the sugar. In some embodiments, a modified sugar may also include non-natural alternative carbon structures such as those present in locked nucleic acids (“LNA”; see, e.g., Koshkin et al. TETRAHEDON (1998); 54: 3607-30), unlocked nucleic acids (“UNA”; see, e.g., Snead et al. MOL. THER-NUCL. ACIDS (2013); 2: e103) and bridged nucleic acids (“BNA”; see, e.g., Imanishi & Obika CHEM. COMMUN. (CAMB) (2002); 21: 1653-59).

In some embodiments, a nucleotide modification in a sugar comprises a 2′-modification. In some embodiments, a 2′-modification may be 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-fluoro (2′-F), 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA) or 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA). In some embodiments, the modification is 2′-F, 2′-OMe or 2′-MOE. In some embodiments, a modification in a sugar comprises a modification of the sugar ring, which may comprise modification of one or more carbons of the sugar ring. For example, a modification of a sugar of a nucleotide may comprise a 2′-oxygen of a sugar is linked to a 1′-carbon or 4′-carbon of the sugar, or a 2′-oxygen is linked to the 1′-carbon or 4′-carbon via an ethylene or methylene bridge. In some embodiments, a modified nucleotide has an acyclic sugar that lacks a 2′-carbon to 3′-carbon bond. In some embodiments, a modified nucleotide has a thiol group, e.g., in the 4′ position of the sugar.

In some embodiments, an oligonucleotide (e.g., an RNAi oligonucleotide) described herein comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, or more). In some embodiments, the sense strand of the oligonucleotide comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, or more). In some embodiments, the antisense strand of the oligonucleotide comprises at least about 1 modified nucleotide (e.g., at least 1, at least 5, at least 10, at least 15, at least 20, or more).

In some embodiments, all the nucleotides of the sense strand of the oligonucleotide are modified. In some embodiments, all the nucleotides of the antisense strand of the oligonucleotide are modified. In some embodiments, all the nucleotides of the oligonucleotide (i.e., both the sense strand and the antisense strand) are modified. In some embodiments, the modified nucleotide comprises a 2′-modification (e.g., a 2′-F or 2′-OMe, 2′-MOE, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid).

In some embodiments, the disclosure provides oligonucleotides having different modification patterns. In some embodiments, an oligonucleotide herein comprises a sense strand having a modification pattern as set forth in the Examples and Sequence Listing and an antisense strand having a modification pattern as set forth in the Examples and Sequence Listing.

In some embodiments, an oligonucleotide disclosed herein (e.g., an RNAi oligonucleotide) comprises an antisense strand having nucleotides that are modified with 2′-F. In some embodiments, an oligonucleotide herein comprises an antisense strand comprising nucleotides that are modified with 2′-F and 2′-OMe. In some embodiments, an oligonucleotide disclosed herein comprises a sense strand having nucleotides that are modified with 2′-F. In some embodiments, an oligonucleotide disclosed herein comprises a sense strand comprises nucleotides that are modified with 2′-F and 2′-OMe.

In some embodiments, an oligonucleotide described herein comprises a sense strand with about 10-15%, 10%, 11%, 12%, 13%, 14%, or 15% of the nucleotides of the sense strand comprising a 2′-fluoro modification. In some embodiments, about 11% of the nucleotides of the sense strand comprise a 2-fluoro modification. In some embodiments, an oligonucleotide described herein comprises an antisense strand with about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the antisense strand comprising a 2′-fluoro modification. In some embodiments, about 32% of the nucleotides of the antisense strand comprise a 2′-fluoro modification. In some embodiments, the oligonucleotide has about 15-25%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of its nucleotides comprising a 2′-fluoro modification. In some embodiments, about 19% of the nucleotides in the dsRNAi oligonucleotide comprise a 2′-fluoro modification.

In some embodiments, one or more of positions 8, 9, 10, or 11 of the sense strand is modified with a 2′—F group. In some embodiments, one or more of positions 3, 8, 9, 10, 12, 13, and 17 of the sense strand is modified with a 2′—F group. In some embodiments, one or more of positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand is modified with a 2′—F group. In some embodiments, one or more of positions 2, 3, 4, 5, 7, 8, 10, 14, 16, and 19 is modified with a 2′—F group. In some embodiments, the sugar moiety at each of nucleotides at positions 1-7 and 12-20 in the sense strand is modified with a 2′-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 1-7, 12-27, and 31-36 in the sense strand is modified with a 2′-OMe. In some embodiments, the sugar moiety at each of nucleotides at positions 6, 9, 11-13, 15, 17, 18, and 20-22 in the sense strand is modified with a 2′-OMe.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein one or more of positions 8, 9, 10 or 11 of the sense strand is modified with a 2′—F group.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively, and; (d) SEQ ID NOs: 813 and 901, respectively, wherein one or more of positions 8, 9, 10, or 11 of the sense strand is modified with a 2′—F group.

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 4, 5, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 3, 5, 7, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 1, 2, 3, 5, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 5, 7, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 10, and 14 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety of each of the nucleotides at positions 2, 3, 4, 5, 7, 8, 10, 14, 16, and 19 of the antisense strand modified with 2′-F and the sugar moiety of each of the remaining nucleotides of the antisense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with 2′-F.

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with 2′-OMe.

In some embodiments, an oligonucleotide provided herein comprises an antisense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, or position 22 modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 8-11 modified with 2′-F. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 3, 8, 9, 10, 12, 13 and 17 modified with 2′-F. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1-7 and 12-17 or 12-20 modified with 2′OMe. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 1-7 and 12-17 or 12-20 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA). In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at positions 1-2, 4-7, 11, 14-16, and 18-20 modified with 2′OMe. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety of each of the nucleotides at positions 1-2, 4-7, 11, 14-16, and 18-20 of the sense strand modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with 2′-F. In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with 2′-OMe.

In some embodiments, an oligonucleotide provided herein comprises a sense strand having the sugar moiety at position 1, position 2, position 3, position 4, position 5, position 6, position 7, position 8, position 9, position 10, position 11, position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21, position 22, position 23, position 24, position 25, position 26, position 27, position 28, position 29, position 30, position 31, position 32, position 33, position 34, position 35, or position 36 modified with a modification selected from the group consisting of 2′-O-propargyl, 2′-O-propylamin, 2′-amino, 2′-ethyl, 2′-aminoethyl (EA), 2′-O-methyl (2′-OMe), 2′-O-methoxyethyl (2′-MOE), 2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid (2′-FANA).

5′-Terminal Phosphate

In some embodiments, an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a sense strand and an antisense strand, wherein the antisense strand comprises a 5′-terminal phosphate. In some embodiments, 5′-terminal phosphate groups of an RNAi oligonucleotide enhance the interaction with Ago2. However, oligonucleotides comprising a 5′-phosphate group may be susceptible to degradation via phosphatases or other enzymes, which can limit their performance and/or bioavailability in vivo. In some embodiments, an oligonucleotide herein includes analogs of 5′ phosphates that are resistant to such degradation. In some embodiments, the phosphate analog is oxymethylphosphonate, vinylphosphonate or malonylphosphonate, or a combination thereof. In certain embodiments, the 5′ terminus of an oligonucleotide strand is attached to chemical moiety that mimics the electrostatic and steric properties of a natural 5′-phosphate group (“phosphate mimic”). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein the oligonucleotide comprises a 5′-terminal phosphate, optionally a 5′-terminal phosphate analog.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively, wherein the oligonucleotide comprises a 5′-terminal phosphate, optionally a 5′-terminal phosphate analog.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) has a phosphate analog at a 4′-carbon position of the sugar (referred to as a “4′-phosphate analog”). See, e.g., Intl. Patent Application Publication No. WO 2018/045317. In some embodiments, an oligonucleotide herein comprises a 4′-phosphate analog at a 5′-terminal nucleotide. In some embodiments, a phosphate analog is an oxymethylphosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar moiety (e.g., at its 4′-carbon) or analog thereof. In other embodiments, a 4′-phosphate analog is a thiomethylphosphonate or an aminomethylphosphonate, in which the sulfur atom of the thiomethyl group or the nitrogen atom of the amino methyl group is bound to the 4′-carbon of the sugar moiety or analog thereof. In certain embodiments, a 4′-phosphate analog is an oxymethylphosphonate. In some embodiments, an oxymethylphosphonate is represented by the formula —O—CH₂—PO(OH)₂, —O—CH₂—PO(OR)₂, or —O—CH₂—PO(OH)(R), in which R is independently selected from —H, —CH₃, an alkyl group, —CH₂CH₂CN, —CH₂OCOC(CH₃)₃, —CH₂OCH₂CH₂Si(CH₃)₃ or a protecting group. In certain embodiments, the alkyl group is —CH₂CH₃. More typically, R is independently selected from H, —CH₃ or —CH₂CH₃. In some embodiment, R is —CH₃. In some embodiments, the 4′-phosphate analog is 5′-methoxyphosphonate-4′-oxy.

In some embodiments, an oligonucleotide provided herein comprises an antisense strand comprising a 4′-phosphate analog at the 5′-terminal nucleotide, wherein 5′-terminal nucleotide comprises the following structure (Chem. formula 1).

5′-methoxyphosphonate-4′-oxy-2′-O-methyluridine phosphorothioate [MePhosphonate-40-mUs]

Modified Internucleotide Linkage

In some embodiments, an oligonucleotide provided herein (e.g., a RNAi oligonucleotide) comprises a modified internucleotide linkage. In some embodiments, phosphate modifications or substitutions result in an oligonucleotide that comprises at least about 1 (e.g., at least 1, at least 2, at least 3, or at least 5) modified internucleotide linkage. In some embodiments, any one of the oligonucleotides disclosed herein comprises about 1 to about 10 (e.g., 1 to 10, 2 to 8, 4 to 6, 3 to 10, 5 to 10, 1 to 5, 1 to 3, or 1 to 2) modified internucleotide linkages. In some embodiments, any one of the oligonucleotides disclosed herein comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 modified internucleotide linkages.

A modified internucleotide linkage may be a phosphorodithioate linkage, a phosphorothioate linkage, a phosphotriester linkage, a thionoalkylphosphonate linkage, a thionalkylphosphotriester linkage, a phosphoramidite linkage, a phosphonate linkage or a boranophosphate linkage. In some embodiments, at least one modified internucleotide linkage of any one of the oligonucleotides as disclosed herein is a phosphorothioate linkage.

In some embodiments, an oligonucleotide provided herein (e.g., a RNAi oligonucleotide) has a phosphorothioate linkage between one or more of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 3 and 4 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein the oligonucleotide comprises a modified internucleotide linkage.

In some embodiments, the oligonucleotide described herein has a phosphorothioate linkage between each of positions 1 and 2 of the sense strand, positions 1 and 2 of the antisense strand, positions 2 and 3 of the antisense strand, positions 20 and 21 of the antisense strand, and positions 21 and 22 of the antisense strand. In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively, and; (d) SEQ ID NOs: 813 and 901, respectively, wherein the oligonucleotide comprises a modified internucleotide linkage.

Base Modifications

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotides) comprises one or more modified nucleobases. In some embodiments, modified nucleobases (also referred to herein as base analogs) are linked at the 1′ position of a nucleotide sugar moiety. In certain embodiments, a modified nucleobase is a nitrogenous base. In some embodiments, a modified nucleobase does not contain nitrogen atom. See, e.g., US Patent Application Publication No. 2008/0274462. In some embodiments, a modified nucleotide comprises a universal base. In some embodiments, a modified nucleotide does not contain a nucleobase (abasic). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein the oligonucleotide comprises one or more modified nucleobases.

In some embodiments, a modified nucleotide comprises a universal base. In some embodiments, a modified nucleotide does not contain a nucleobase (abasic). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively, wherein the oligonucleotide comprises one or more modified nucleobases.

In some embodiments, a universal base is a heterocyclic moiety located at the 1′ position of a nucleotide sugar moiety in a modified nucleotide, or the equivalent position in a nucleotide sugar moiety substitution, that, when present in a duplex, can be positioned opposite more than one type of base without substantially altering structure of the duplex. In some embodiments, compared to a reference single-stranded nucleic acid (e.g., oligonucleotide) that is fully complementary to a target nucleic acid (e.g., a NR1H3 mRNA), a single-stranded nucleic acid containing a universal base forms a duplex with the target nucleic acid that has a lower T_(m) than a duplex formed with the complementary nucleic acid. In some embodiments, when compared to a reference single-stranded nucleic acid in which the universal base has been replaced with a base to generate a single mismatch, the single-stranded nucleic acid containing the universal base forms a duplex with the target nucleic acid that has a higher T_(m) than a duplex formed with the nucleic acid comprising the mismatched base.

Non-limiting examples of universal-binding nucleotides include, but are not limited to, inosine, 1-β-D-ribofuranosyl-5-nitroindole and/or 1-β-D-ribofuranosyl-3-nitropyrrole (see, US Patent Application Publication No. 2007/0254362; Van Aerschot et al. NUCLEIC ACIDS RES. (1995); 23: 4363-4370; Loakes et al. NUCLEIC ACIDS RES. (1995); 23: 2361-66; and Loakes & Brown NUCLEIC ACIDS RES. (1994); 22: 4039-43).

Targeting Ligands

In some embodiments, it is desirable to target an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) to one or more cells or cell type, tissues, organs, or anatomical regions or compartments. Such a strategy may help to avoid undesirable effects and/or to avoid undue loss of the oligonucleotide to cells, tissues, organs, or anatomical regions or compartments that would not benefit from the oligonucleotide or its effects (e.g., inhibition or reduction of NR1H3 expression). Accordingly, in some embodiments, oligonucleotides disclosed herein (e.g., RNAi oligonucleotides) are modified to facilitate targeting and/or delivery to particular cells or cell types, tissues, organs, or anatomical regions or compartments (e.g., to facilitate delivery of the oligonucleotide to the liver). In some embodiments, an oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6, or more nucleotides) conjugated to one or more targeting ligand(s). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein the oligonucleotide comprises a targeting ligand conjugated to at least one nucleotide.

In some embodiments, an oligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5, 6, or more nucleotides) conjugated to one or more targeting ligand(s). In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively, and; (d) SEQ ID NOs: 813 and 901, respectively, wherein the oligonucleotide comprises a targeting ligand conjugated to at least one nucleotide.

In some embodiments, the targeting ligand comprises a carbohydrate, amino sugar, cholesterol, peptide, polypeptide, protein, or part of a protein (e.g., an antibody or antibody fragment), or lipid. In certain embodiments, the targeting ligand is a carbohydrate comprising at least one GalNAc moiety.

In some embodiments, 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides of an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) are each conjugated to a separate targeting ligand (e.g., a GalNAc moiety). In some embodiments, 2 to 4 nucleotides of an oligonucleotide are each conjugated to a separate targeting ligand. In some embodiments, targeting ligands are conjugated to 2 to 4 nucleotides at either ends of the sense or antisense strand (e.g., targeting ligands are conjugated to a 2 to 4 nucleotide overhang or extension on the 5′ or 3′ terminus of the sense or antisense strand) such that the targeting ligands resemble bristles of a toothbrush and the oligonucleotide resembles a toothbrush. For example, an oligonucleotide may comprise a stem-loop at either the 5′ or 3′ terminus of the sense strand and 1, 2, 3, or 4 nucleotides of the loop of the stem may be individually conjugated to a targeting ligand. In some embodiments, an oligonucleotide provided by the disclosure (e.g., a RNAi oligonucleotide) comprises a stem-loop at the 3′ terminus of the sense strand, wherein the loop of the stem-loop comprises a triloop or a tetraloop, and wherein the 3 or 4 nucleotides comprising the triloop or tetraloop, respectively, are individually conjugated to a targeting ligand. In some embodiments, an oligonucleotide provided by the disclosure (e.g., a RNAi oligonucleotide) comprises a stem-loop at the 3′ terminus of the sense strand, wherein the loop of the stem-loop comprises a tetraloop, and wherein 3 nucleotides of the tetraloop are individually conjugated to a targeting ligand.

GalNAc is a high affinity carbohydrate ligand for the asialoglycoprotein receptor (ASGPR), which is primarily expressed on the surface of hepatocyte cells and has a major role in binding, internalizing and subsequent clearing circulating glycoproteins that contain terminal galactose or GalNAc residues (asialoglycoproteins). Conjugation (either indirect or direct) of GalNAc moieties to oligonucleotides of the instant disclosure can be used to target these oligonucleotides to the ASGPR expressed on cells. In some embodiments, an oligonucleotide of the instant disclosure (e.g., an RNAi oligonucleotide) is conjugated to at least one or more GalNAc moieties, wherein the GalNAc moieties target the oligonucleotide to an ASGPR expressed on human liver cells (e.g., human hepatocytes). In some embodiments, the GalNAc moiety target the oligonucleotide to the liver.

In some embodiments, an oligonucleotide of the instant disclosure (e.g., an RNAi oligonucleotide) is conjugated directly or indirectly to a monovalent GalNAc moiety. In some embodiments, the oligonucleotide is conjugated directly or indirectly to more than one monovalent GalNAc (i.e., is conjugated to 2, 3, or 4 monovalent GalNAc moieties and is typically conjugated to 3 or 4 monovalent GalNAc moieties). In some embodiments, an oligonucleotide is conjugated to one or more bivalent GalNAc, trivalent GalNAc or tetravalent GalNAc moieties. In some embodiments, a bivalent, trivalent or tetravalent GalNAc moiety is conjugated to an oligonucleotide via a branched linker. In some embodiments, a monovalent GalNAc moiety is conjugated to a first nucleotide and a bivalent, trivalent, or tetravalent GalNAc moiety is conjugated to a second nucleotide via a branched linker.

In some embodiments, one (1) or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotides of an oligonucleotide described herein (e.g., an RNAi oligonucleotide) are each conjugated to a GalNAc moiety. In some embodiments, two (2) to four (4) nucleotides of a tetraloop are each conjugated to a separate GalNAc moiety. In some embodiments, one (1) to three (3) nucleotides of a triloop are each conjugated to a separate GalNAc moiety. In some embodiments, targeting ligands are conjugated to two (2) to four (4) nucleotides at either ends of the sense or antisense strand (e.g., ligands are conjugated to a two (2) to four (4) nucleotide overhang or extension on the 5′ or 3′ terminus of the sense or antisense strand) such that the GalNAc moieties resemble bristles of a toothbrush and the oligonucleotide resembles a toothbrush. In some embodiments, GalNAc moieties are conjugated to a nucleotide of the sense strand. For example, three (3) or four (4) GalNAc moieties can be conjugated to nucleotides in the tetraloop of the sense strand where each GalNAc moiety is conjugated to one (1) nucleotide.

In some embodiments, an oligonucleotide described herein (e.g., an RNAi oligonucleotide) comprises a tetraloop, wherein the tetraloop (L) is any combination of adenine (A) and guanine (G) nucleotides. In some embodiments, the tetraloop (L) comprises a monovalent GalNAc moiety attached to any one or more guanine (G) nucleotides of the tetraloop via any linker described herein, as depicted below (X=heteroatom) in Chem. formula 2:

In some embodiments, the tetraloop (L) has a monovalent GalNAc attached to any one or more adenine nucleotides of the tetraloop via any linker described herein, as depicted below (X=heteroatom) in Chem. formula 3:

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide) comprises a monovalent GalNAc moiety attached to a guanine (G) nucleotide referred to as [ademG-GalNAc] or 2′-aminodiethoxymethanol-Guanine-GalNAc, as depicted below in Chem. formula 4:

In some embodiments, an oligonucleotide herein comprises a monovalent GalNAc moiety attached to an adenine nucleotide, referred to as [ademA-GalNAc] or 2′-aminodiethoxymethanol-Adenine-GalNAc, as depicted below Chem. formula 5:

An example of such conjugation is shown below for a loop comprising from 5′ to 3′ the nucleotide sequence GAAA (L=linker, X=heteroatom). Such a loop may be present, for example, at positions 27-30 of a sense strand provided herein. In the Chem. formula 6 is used to describe an attachment point to the oligonucleotide strand.

Appropriate methods or chemistry (e.g., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide comprising an oligonucleotide herein (e.g., an RNAi oligonucleotide) using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein. Acetal-based linkers are disclosed, for example, in Intl. Patent Application Publication No. WO2016/100401. In some embodiments, the linker is a labile linker. However, in other embodiments, the linker is stable. An example is shown below for a loop comprising from 5′ to 3′ the nucleotides GAAA, in which GalNAc moieties are attached to nucleotides of the loop using an acetal linker. Such a loop may be present, for example, at positions 27-30 of the any one of the sense strands. In the Chem. formula 7 is an attachment point to the oligonucleotide strand.

As mentioned, various appropriate methods or chemistry synthetic techniques (e.g., click chemistry) can be used to link a targeting ligand to a nucleotide. In some embodiments, a targeting ligand is conjugated to a nucleotide using a click linker. In some embodiments, an acetal-based linker is used to conjugate a targeting ligand to a nucleotide of any one of the oligonucleotides described herein. Acetal-based linkers are disclosed, for example, in Intl. Patent Application Publication No. WO 2016/100401. In some embodiments, the linker is a labile linker. However, in other embodiments, the linker is a stable linker.

In some embodiments, a duplex extension (e.g., of up to 3, 4, 5, or 6 bp in length) is provided between a targeting ligand (e.g., a GalNAc moiety) and the oligonucleotide. In some embodiments, the oligonucleotides herein (e.g., RNAi oligonucleotides) do not have a GalNAc conjugated thereto.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively, wherein the oligonucleotide comprises at least one GalNAc moiety conjugated to a nucleotide.

In some embodiments, the sense and antisense strands of an oligonucleotide comprise nucleotides sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively, wherein the oligonucleotide comprises at least one GalNAc moiety conjugated to a nucleotide.

Exemplary Oligonucleotides for Reducing NR1H3 Expression

In some embodiments, the NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression provided by the disclosure comprise a sense strand and an antisense strand, wherein all nucleotides comprising the sense strand and antisense strand are modified, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length. In some embodiments, the 5′-terminal nucleotide of the antisense strand comprises 5′-methoxyphosphonate-4′-oxy-2′-O-methyluridine [MePhosphonate-4O-mU], as described herein. In some embodiments, the 5′-terminal nucleotide of the antisense strand comprises a phosphorothioate linkage. In some embodiments, the antisense strand and the sense strand comprise one or more 2′-fluoro (2′-F) and 2′-O-methyl (2′-OMe) modified nucleotides and at least one phosphorothioate linkage. In some embodiments, the antisense strand comprises four (4) phosphorothioate linkages and the sense strand comprises one (1) phosphorothioate linkage. In some embodiments, the antisense strand comprises five (5) phosphorothioate linkages and the sense strand comprises one (1) phosphorothioate linkage.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 1-384 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 385-768.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 769-856 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 857-944.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 1519-1552 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 857-944.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) comprises a sense strand having a sequence of any one of SEQ ID NOs: 945-1032 and an antisense strand comprising a complementary sequence selected from SEQ ID NOs: 1033-1120.

In some embodiments, an oligonucleotide provided herein (e.g., and RNAi oligonucleotide) for reducing NR1H3 expression comprises:

a sense strand comprising a 2′-F modified nucleotide at positions 8-11, a 2′-OMe modified nucleotide at positions 1-7, 12-27, and 31-36, a GalNAc-conjugated nucleotide at position 28, 29 and 30; and a phosphorothioate linkage between positions 1 and 2;

an antisense strand comprising a 2′-F modified nucleotide at positions 2, 3, 4, 5, 7, 10 and 14, a 2′-OMe at positions 1, 6, 8, 9, 11-13, and 15-22, a phosphorothioate linkage between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 20 and 21, and positions 21 and 22, and a 5′-terminal nucleotide at position 1 comprising a 4′-phosphate analog, optionally wherein the 5′-terminal nucleotide comprises 5′-methoxyphosphonate-4′-oxy-2′-O-methyluridine [MePhosphonate-4O-mU]; wherein positions 1-20 of the antisense strand form a duplex region with positions 1-20 of the sense strand, wherein positions 21-36 of the sense strand form a stem-loop, wherein positions 27-30 form the loop of the stem-loop, optionally wherein positions 27-30 comprise a tetraloop, wherein positions 21 and 22 of the antisense strand comprise an overhang, and wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively,

In some embodiments, the NR1H3-targeting dsRNAi oligonucleotides for reducing NR1H3 expression comprise:

a sense strand comprising a 2′-F modified nucleotide at positions 8-11, a 2′-OMe modified nucleotide at positions 1-7, 12-27, and 31-36, a GalNAc-conjugated nucleotide at position 28, 29 and 30; and a phosphorothioate linkage between positions 1 and 2;

an antisense strand comprising a 2′-F modified nucleotide at positions 2, 3, 4, 5, 7, 10 and 14, a 2′-OMe at positions 1, 6, 8, 9, 11-13, and 15-22, a phosphorothioate linkage between positions 1 and 2, positions 2 and 3, positions 3 and 4, positions 20 and 21, and positions 21 and 22, and a 5′-terminal nucleotide at position 1 comprising a 4′-phosphate analog, optionally wherein the 5′-terminal nucleotide comprises 5′-methoxyphosphonate-4′-oxy-2′-O-methyluridine [MePhosphonate-4O-mU]; wherein positions 1-20 of the antisense strand form a duplex region with positions 1-20 of the sense strand, wherein positions 21-36 of the sense strand form a stem-loop, wherein positions 27-30 form the loop of the stem-loop, optionally wherein positions 27-30 comprise a tetraloop, wherein positions 21 and 22 of the antisense strand comprise an overhang, and wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 786 and 874, respectively; (b) SEQ ID NOs: 787 and 875, respectively; (c) SEQ ID NOs: 1537 and 929, respectively; and, (d) SEQ ID NOs: 813 and 901, respectively.

In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 786 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 874. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 787 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 875. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1537 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 929. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 813 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 901.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1512; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1513; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1515; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1512; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1513; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1515; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1512; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1509, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1513; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1510, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1409, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1515; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1511, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1512; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1509, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1513; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1510, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1514; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1409, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, a NR1H3-targeting dsRNAi oligonucleotide for reducing NR1H3 expression comprises (i) an antisense strand of 19-30 nucleotides in length, wherein the antisense strand comprises a nucleotide sequence comprising a region of complementarity to a NR1H3 mRNA target sequence, wherein the region of complementarity is set forth in SEQ ID NO: 1515; and (ii) a sense strand of 19-50 nucleotides in length comprising a region of complementarity to the antisense strand and a stem-loop at the 3′terminus, wherein the region of complementarity to the antisense strand is set forth in SEQ ID NO: 1511, wherein the stem-loop is set forth as S1-L-S2, wherein S1 is complementary to S2 and wherein L forms a loop between S1 and S2 of 3 to 5 nucleotides in length, wherein the antisense and sense strands are separate strands which form an asymmetric duplex region having an overhang of 1-4 nucleotides at the 3′ terminus of the antisense strand.

In some embodiments, the disclosure provides an oligonucleotide (e.g., an RNAi oligonucleotide) for reducing NR1H3 expression, wherein the oligonucleotide comprises a sense strand and an antisense strand according to:

Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mX-mX-mX-mX-mX-mX-3′; hybridized to:

Antisense Strand: 5′-[MePhosphonate-40-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′;

wherein mX=2′-O-methyl modified nucleotide, fX=2′-fluoro modified nucleotide, -S-=phosphorothioate linkage, -=phosphodiester linkage, [MePhosphonate-40-mX]=5′-methoxyphosphonate-4-oxy modified nucleotide, and ademA-GalNAc=GalNAc attached to an adenine nucleotide.

In some embodiments, the disclosure provides an oligonucleotide (e.g., an RNAi oligonucleotide) for reducing NR1H3 expression, wherein the oligonucleotide comprises a sense strand and an antisense strand according to:

Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mX-mX-mX-mX-mX-mX-3′; hybridized to:

Antisense Strand: 5′-[MePhosphonate-40-mX]-S-fX-S-fX-S-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′;

wherein mX=2′-O-methyl modified nucleotide, fX=2′-fluoro modified nucleotide, -S-=phosphorothioate linkage, -=phosphodiester linkage, [MePhosphonate-40-mX]=5′-methoxyphosphonate-4-oxy modified nucleotide, and ademA-GalNAc=GalNAc attached to an adenine nucleotide.

In some embodiments, the disclosure provides an oligonucleotide (e.g., an RNAi oligonucleotide) for reducing NR1H3 expression, wherein the oligonucleotide comprises a sense strand and an antisense strand comprising nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 945 and 1033, respectively; (b) SEQ ID NOs: 946 and 1034, respectively; (c) SEQ ID NOs: 947 and 1035, respectively; (d) SEQ ID NOs: 948 and 1036, respectively; (e) SEQ ID NOs: 949 and 1037, respectively; (f) SEQ ID NOs: 950 and 1038, respectively; (g) SEQ ID NOs: 951 and 1039, respectively; (h) SEQ ID NOs: 952 and 1040, respectively; (i) SEQ ID NOs: 953 and 1041, respectively; (j) SEQ ID NOs: 954 and 1042, respectively; (k) SEQ ID NOs: 955 and 1043, respectively; (l) SEQ ID NOs: 956 and 1044 respectively; (m) SEQ ID NOs: 957 and 1045, respectively; (n) SEQ ID NOs: 958 and 1046, respectively; (o) SEQ ID NOs: 959 and 1047, respectively; (p) SEQ ID NOs: 960 and 1048, respectively; (q) SEQ ID NOs: 961 and 1049, respectively; (r) SEQ ID NOs: 962 and 1050, respectively; (s) SEQ ID NOs: 963 and 1051, respectively; (t) SEQ ID NOs: 964 and 1052, respectively; (u) SEQ ID NOs: 965 and 1053, respectively; (v) SEQ ID NOs: 966 and 1054, respectively; (w) SEQ ID NOs: 967 and 1055, respectively; (x) SEQ ID NOs: 968 and 1056, respectively; (y) SEQ ID NOs: 969 and 1057, respectively; (z) SEQ ID NOs: 970 and 1058, respectively; (aa) SEQ ID NOs: 971 and 1059, respectively; (bb) SEQ ID NOs: 972 and 1060, respectively; (cc) SEQ ID NOs: 973 and 1061, respectively; (dd) SEQ ID NOs: 974 and 1062, respectively; (ee) SEQ ID NOs: 975 and 1063, respectively; (ff) SEQ ID NOs: 976 and 1064, respectively; (gg) SEQ ID NOs: 977 and 1065, respectively; (hh) SEQ ID NOs: 978 and 1066, respectively; (ii) SEQ ID NOs: 979 and 1067, respectively; (jj) SEQ ID NOs: 980 and 1068, respectively; (kk) SEQ ID NOs: 981 and 1069, respectively; (ll) SEQ ID NOs: 982 and 1070, respectively; (mm) SEQ ID NOs: 983 and 1071, respectively; (nn) SEQ ID NOs: 984 and 1072, respectively; (oo) SEQ ID NOs: 985 and 1073, respectively; (pp) SEQ ID NOs: 986 and 1074, respectively; (qq) SEQ ID NOs: 987 and 1075, respectively; (rr) SEQ ID NOs: 988 and 1076, respectively; (ss) SEQ ID NOs: 989 and 1077, respectively; (tt) SEQ ID NOs: 990 and 1078, respectively; (uu) SEQ ID NOs: 991 and 1079, respectively; (vv) SEQ ID NOs: 992 and 1080, respectively; (ww) SEQ ID NOs: 993 and 1081, respectively; (xx) SEQ ID NOs: 994 and 1082, respectively; (yy) SEQ ID NOs: 995 and 1083, respectively; (zz) SEQ ID NOs: 996 and 1084, respectively; (aaa) SEQ ID NOs: 997 and 1085, respectively; (bbb) SEQ ID NOs: 998 and 1086, respectively; (ccc) SEQ ID NOs: 999 and 1087, respectively; (ddd) SEQ ID NOs: 1000 and 1088, respectively; (eee) SEQ ID NOs: 1001 and 1089, respectively; (fff) SEQ ID NOs: 1002 and 1090, respectively; (ggg) SEQ ID NOs: 1003 and 1091, respectively; (hhh) SEQ ID NOs: 1004 and 1092 respectively; (iii) SEQ ID NOs: 1005 and 1093 respectively; (jjj) SEQ ID NOs: 1006 and 1094, respectively; (kkk) SEQ ID NOs: 1007 and 1095, respectively; (lll) SEQ ID NOs: 1008 and 1096, respectively; (mmm) SEQ ID NOs: 1009 and 1097, respectively; (nnn) SEQ ID NOs: 1010 and 1098, respectively; (ooo) SEQ ID NOs: 1011 and 1099, respectively; (ppp) SEQ ID NOs: 1012 and 1100, respectively; (qqq) SEQ ID NOs: 1013 and 1101, respectively; (rrr) SEQ ID NOs: 1014 and 1102 respectively; (sss) SEQ ID NOs: 1015 and 1103, respectively; (ttt) SEQ ID NOs: 1016 and 1104, respectively; (uuu) SEQ ID NOs: 1017 and 1105, respectively; (vvv) SEQ ID NOs: 1018 and 1106, respectively; (www) SEQ ID NOs: 1019 and 1107, respectively; (xxx) SEQ ID NOs: 1020 and 1108, respectively; (yyy) SEQ ID NOs: 1021 and 1109, respectively; (zzz) SEQ ID NOs: 1022 and 1110, respectively; (aaaa) SEQ ID NOs: 1023 and 1111, respectively; (bbbb) SEQ ID NOs: 1024 and 1112, respectively; (cccc) SEQ ID NOs: 1025 and 1113, respectively; (dddd) SEQ ID NOs: 1026 and 1114, respectively; (eeee) SEQ ID NOs: 1027 and 1115, respectively; (ffff) SEQ ID NOs: 1028 and 1116, respectively; (gggg) SEQ ID NOs: 1029 and 1117, respectively; (hhhh) SEQ ID NOs: 1030 and 1118, respectively; (iiii) SEQ ID NOs: 1031 and 1119, respectively; and, (jjjj) SEQ ID NOs: 1032 and 1120, respectively.

In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 963 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1051. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 964 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1052. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1006 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1094. In some embodiments, a NR1H3-targeting oligonucleotide for reducing NR1H3 expression provided by the disclosure comprises a sense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1018 and an antisense strand comprising the nucleotide sequence as set forth in SEQ ID NO: 1106.

Formulations

Various formulations (e.g., pharmaceutical formulations) have been developed for oligonucleotide use. For example, oligonucleotides (e.g., RNAi oligonucleotides) can be delivered to a subject or a cellular environment using a formulation that minimizes degradation, facilitates delivery and/or uptake, or provides another beneficial property to the oligonucleotides in the formulation. In some embodiments, provided herein are compositions comprising oligonucleotides (e.g., RNAi oligonucleotides) reduce the expression of NR1H3. Such compositions can be suitably formulated such that when administered to a subject, either into the immediate environment of a target cell or systemically, a sufficient portion of the oligonucleotides enter the cell to reduce NR1H3 expression. Any variety of suitable oligonucleotide formulations can be used to deliver oligonucleotides for the reduction of NR1H3 as disclosed herein. In some embodiments, an oligonucleotide is formulated in buffer solutions such as phosphate buffered saline solutions, liposomes, micellar structures, and capsids. Any of the oligonucleotides described herein may be provided not only as nucleic acids, but also in the form of a pharmaceutically acceptable salt.

Formulations of oligonucleotides with cationic lipids can be used to facilitate transfection of the oligonucleotides into cells. For example, cationic lipids, such as lipofectin, cationic glycerol derivatives, and polycationic molecules (e.g., polylysine), can be used. Suitable lipids include Oligofectamine, Lipofectamine (Life Technologies), NC388 (Ribozyme Pharmaceuticals, Inc., Boulder, Colo.), or FuGene 6 (Roche) all of which can be used according to the manufacturer's instructions.

Accordingly, in some embodiments, a formulation comprises a lipid nanoparticle. In some embodiments, an excipient comprises a liposome, a lipid, a lipid complex, a microsphere, a microparticle, a nanosphere or a nanoparticle, or may be otherwise formulated for administration to the cells, tissues, organs, or body of a subject in need thereof (see, e.g., Remington: THE SCIENCE AND PRACTICE OF PHARMACY, 22nd edition, Pharmaceutical Press, 2013).

In some embodiments, the formulations herein comprise an excipient. In some embodiments, an excipient confers to a composition improved stability, improved absorption, improved solubility and/or therapeutic enhancement of the active ingredient. In some embodiments, an excipient is a buffering agent (e.g., sodium citrate, sodium phosphate, a tris base, or sodium hydroxide) or a vehicle (e.g., a buffered solution, petrolatum, dimethyl sulfoxide, or mineral oil). In some embodiments, an oligonucleotide is lyophilized for extending its shelf-life and then made into a solution before use (e.g., administration to a subject). Accordingly, an excipient in a composition comprising any one of the oligonucleotides described herein may be a lyoprotectant (e.g., mannitol, lactose, polyethylene glycol or polyvinylpyrrolidone) or a collapse temperature modifier (e.g., dextran, Ficoll™ or gelatin).

In some embodiments, a pharmaceutical composition is formulated to be compatible with its intended route of administration. The route of administration may be any route which effectively transports a compound of this invention to the desired or appropriate place in the body. Examples of routes of administration include parenteral (e.g., intravenous, intramuscular, intraperitoneal, intradermal, subcutaneous), oral (e.g., inhalation), transdermal (e.g., topical), transmucosal and rectal administration.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition. Sterile injectable solutions can be prepared by incorporating the oligonucleotides in a required amount in a selected solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.

In some embodiments, a composition may contain at least about 0.1% of the therapeutic agent (e.g., a RNAi oligonucleotide for reducing NR1H3 expression) or more, although the percentage of the active ingredient(s) may be between about 1% to about 80% or more of the weight or volume of the total composition. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.

Methods of Use Reducing NR1H3 Expression

In some embodiments, the disclosure provides methods for contacting or delivering to a cell or population of cells an effective amount of oligonucleotides provided herein (e.g., RNAi oligonucleotides) to reduce NR1H3 expression. In some embodiments, a reduction of NR1H3 expression is determined by measuring a reduction in the amount or level of NR1H3 mRNA, NR1H3 protein, or NR1H3 activity in a cell. The methods include those described herein and known to one of ordinary skill in the art.

Methods provided herein are useful in any appropriate cell type. In some embodiments, a cell is any cell that expresses NR1H3 mRNA (e.g., hepatocytes). In some embodiments, the cell is a primary cell obtained from a subject. In some embodiments, the primary cell has undergone a limited number of passages such that the cell substantially maintains its natural phenotypic properties. In some embodiments, a cell to which the oligonucleotide is delivered is ex vivo or in vitro (i.e., can be delivered to a cell in culture or to an organism in which the cell resides).

In some embodiments, the oligonucleotides herein (e.g., RNAi oligonucleotides) are delivered to a cell or population of cells using a nucleic acid delivery method known in the art including, but not limited to, injection of a solution containing the oligonucleotides, bombardment by particles covered by the oligonucleotides, exposing the cell or population of cells to a solution containing the oligonucleotides, or electroporation of cell membranes in the presence of the oligonucleotides. Other methods known in the art for delivering oligonucleotides to cells may be used, such as lipid-mediated carrier transport, chemical-mediated transport, and cationic liposome transfection such as calcium phosphate, and others.

In some embodiments, reduction of NR1H3 expression is determined by an assay or technique that evaluates one or more molecules, properties, or characteristics of a cell or population of cells associated with NR1H3 expression, or by an assay or technique that evaluates molecules that are directly indicative of NR1H3 expression in a cell or population of cells (e.g., NR1H3 mRNA or NR1H3 protein). In some embodiments, the extent to which an oligonucleotide provided herein reduces NR1H3 expression is evaluated by comparing NR1H3 expression in a cell or population of cells contacted with the oligonucleotide to an appropriate control (e.g., an appropriate cell or population of cells not contacted with the oligonucleotide or contacted with a control oligonucleotide). In some embodiments, a control amount or level of NR1H3 expression in a control cell or population of cells is predetermined, such that the control amount or level need not be measured in every instance the assay or technique is performed. The predetermined level or value can take a variety of forms. In some embodiments, a predetermined level or value can be single cut-off value, such as a median or mean.

In some embodiments, contacting or delivering an oligonucleotide described herein (e.g., an RNAi oligonucleotide) to a cell or a population of cells results in a reduction in NR1H3 expression in a cell or population of cells not contacted with the oligonucleotide or contacted with a control oligonucleotide. In some embodiments, the reduction in NR1H3 expression is about 1% or lower, about 5% or lower, about 10% or lower, about 15% or lower, about 20% or lower, about 25% or lower, about 30% or lower, about 35% or lower, about 40% or lower, about 45% or lower, about 50% or lower, about 55% or lower, about 60% or lower, about 70% or lower, about 80% or lower, or about 90% or lower relative to a control amount or level of NR1H3 expression. In some embodiments, the control amount or level of NR1H3 expression is an amount or level of NR1H3 mRNA and/or NR1H3 protein in a cell or population of cells that has not been contacted with an oligonucleotide herein. In some embodiments, the effect of delivery of an oligonucleotide herein to a cell or population of cells according to a method herein is assessed after any finite period or amount of time (e.g., minutes, hours, days, weeks, months). For example, in some embodiments, NR1H3 expression is determined in a cell or population of cells at least about 4 hours, about 8 hours, about 12 hours, about 18 hours, about 24 hours; or at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, about 56 days, about 63 days, about 70 days, about 77 days, or about 84 days or more after contacting or delivering the oligonucleotide to the cell or population of cells. In some embodiments, NR1H3 expression is determined in a cell or population of cells at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months or more after contacting or delivering the oligonucleotide to the cell or population of cells.

In some embodiments, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide) is delivered in the form of a transgene that is engineered to express in a cell the oligonucleotide or strands comprising the oligonucleotide (e.g., its sense and antisense strands). In some embodiments, an oligonucleotide herein is delivered using a transgene engineered to express any oligonucleotide disclosed herein. Transgenes may be delivered using viral vectors (e.g., adenovirus, retrovirus, vaccinia virus, poxvirus, adeno-associated virus, or herpes simplex virus) or non-viral vectors (e.g., plasmids or synthetic mRNAs). In some embodiments, transgenes can be injected directly to a subject.

Treatment Methods

The disclosure provides oligonucleotides (e.g., RNAi oligonucleotides) for use as a medicament, in particular for use in a method for the treatment of diseases, disorders, and conditions associated with expression of NR1H3. The disclosure also provides oligonucleotides for use, or adaptable for use, to treat a subject (e.g., a human having a disease, disorder or condition associated with NR1H3 expression) that would benefit from reducing NR1H3 expression. In some respects, the disclosure provides oligonucleotides for use, or adapted for use, to treat a subject having a disease, disorder or condition associated with expression of NR1H3. The disclosure also provides oligonucleotides for use, or adaptable for use, in the manufacture of a medicament or pharmaceutical composition for treating a disease, disorder or condition associated with NR1H3 expression. In some embodiments, the oligonucleotides for use, or adaptable for use, target NR1H3 mRNA and reduce NR1H3 expression (e.g., via the RNAi pathway). In some embodiments, the oligonucleotides for use, or adaptable for use, target NR1H3 mRNA and reduce the amount or level of NR1H3 mRNA, NR1H3 protein and/or NR1H3 activity.

In addition, in some embodiments of the methods herein, a subject having a disease, disorder, or condition associated with NR1H3 expression or is predisposed to the same is selected for treatment with an oligonucleotide provided herein (e.g., an RNAi oligonucleotide). In some embodiments, the method comprises selecting an individual having a marker (e.g., a biomarker) for a disease, disorder, or condition associated with NR1H3 expression or predisposed to the same, such as, but not limited to, NR1H3 mRNA, NR1H3 protein, or a combination thereof. Likewise, and as detailed below, some embodiments of the methods provided by the disclosure include steps such as measuring or obtaining a baseline value for a marker of NR1H3 expression (e.g., NR1H3 mRNA), and then comparing such obtained value to one or more other baseline values or values obtained after the subject is administered the oligonucleotide to assess the effectiveness of treatment.

The disclosure also provides methods of treating a subject having, suspected of having, or at risk of developing a disease, disorder or condition associated with a NR1H3 expression with an oligonucleotide provided herein. In some respects, the current disclosure provides methods of treating or attenuating the onset or progression of a disease, disorder or condition associated with NR1H3 expression using the oligonucleotides herein. In other aspects, the disclosure provides methods to achieve one or more therapeutic benefits in a subject having a disease, disorder, or condition associated with NR1H3 expression using the oligonucleotides provided herein. In some embodiments of the methods herein, the subject is treated by administering a therapeutically effective amount of any one or more of the oligonucleotides provided herein. In some embodiments, treatment comprises reducing NR1H3 expression. In some embodiments, the subject is treated therapeutically. In some embodiments, the subject is treated prophylactically.

In some embodiments of the methods herein, one or more oligonucleotides herein (e.g., RNAi oligonucleotides), or a pharmaceutical composition comprising one or more oligonucleotides, is administered to a subject having a disease, disorder or condition associated with NR1H3 expression such that NR1H3 expression is reduced in the subject, thereby treating the subject. In some embodiments, an amount or level of NR1H3 mRNA is reduced in the subject. In some embodiments, an amount or level of NR1H3 protein is reduced in the subject. In some embodiments, an amount or level of NR1H3 activity is reduced in the subject.

In some embodiments of the methods herein, an oligonucleotide provided herein (e.g., an RNAi oligonucleotide), or a pharmaceutical composition comprising the oligonucleotide, is administered to a subject having a disease, disorder or condition associated with NR1H3 such that NR1H3 expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to NR1H3 expression prior to administration of one or more oligonucleotides or pharmaceutical composition. In some embodiments, NR1H3 expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to NR1H3 expression in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or oligonucleotides or pharmaceutical composition or receiving a control oligonucleotide or oligonucleotides, pharmaceutical composition or treatment.

In some embodiments of the methods herein, an oligonucleotide or oligonucleotides herein (e.g., RNAi oligonucleotides), or a pharmaceutical composition comprising the oligonucleotide or oligonucleotides, is administered to a subject having a disease, disorder or condition associated with NR1H3 expression such that an amount or level of NR1H3 mRNA is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to the amount or level of NR1H3 mRNA prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of NR1H3 mRNA is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of NR1H3 mRNA in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or oligonucleotides or pharmaceutical composition or receiving a control oligonucleotide or oligonucleotides, pharmaceutical composition or treatment.

In some embodiments of the methods herein, an oligonucleotide or oligonucleotides herein, or a pharmaceutical composition comprising the oligonucleotide or oligonucleotides, is administered to a subject having a disease, disorder or condition associated with NR1H3 expression such that an amount or level of NR1H3 protein is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% or greater than 99% when compared to the amount or level of NR1H3 protein prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of NR1H3 protein is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of NR1H3 protein in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or oligonucleotides or pharmaceutical composition or receiving a control oligonucleotide, oligonucleotides or pharmaceutical composition or treatment.

In some embodiments of the methods herein, an oligonucleotide or oligonucleotides (e.g., RNAi oligonucleotides) herein, or a pharmaceutical composition comprising the oligonucleotide or oligonucleotides, is administered to a subject having a disease, disorder or condition associated with NR1H3 such that an amount or level of NR1H3 gene activity/expression is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to the amount or level of NR1H3 activity prior to administration of the oligonucleotide or pharmaceutical composition. In some embodiments, an amount or level of NR1H3 activity is reduced in the subject by at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greater than 99% when compared to an amount or level of NR1H3 activity in a subject (e.g., a reference or control subject) not receiving the oligonucleotide or pharmaceutical composition or receiving a control oligonucleotide, pharmaceutical composition or treatment.

Suitable methods for determining NR1H3 expression, the amount or level of NR1H3 mRNA, NR1H3 protein, NR1H3 activity, or a biomarker related to or affected by modulation of NR1H3 expression (e.g., a plasma biomarker), in the subject, or in a sample from the subject, are known in the art. Further, the Examples set forth herein illustrate methods for determining NR1H3 expression.

In some embodiments, NR1H3 expression, the amount or level of NR1H3 mRNA, NR1H3 protein, NR1H3 activity, or a biomarker related to or affected by modulation of NR1H3 expression, or any combination thereof, is reduced in a cell (e.g., a hepatocyte), a population or a group of cells (e.g., an organoid), an organ (e.g., liver), blood or a fraction thereof (e.g., plasma), a tissue (e.g., liver tissue), a sample (e.g., a liver biopsy sample), or any other appropriate biological material obtained or isolated from the subject. In some embodiments, NR1H3 expression, the amount or level of NR1H3 mRNA, NR1H3 protein, NR1H3 activity, or a biomarker related to or affected by modulation of NR1H3 expression, or any combination thereof, is reduced in more than one type of cell (e.g., a hepatocyte and one or more other type(s) of cell), more than one groups of cells, more than one organ (e.g., liver and one or more other organ(s)), more than one fraction of blood (e.g., plasma and one or more other blood fraction(s)), more than one type of tissue (e.g., liver tissue and one or more other type(s) of tissue), or more than one type of sample (e.g., a liver biopsy sample and one or more other type(s) of biopsy sample).

Because of their high specificity, the oligonucleotides provided herein (e.g., dsRNAi oligonucleotides) specifically target mRNA of target genes (e.g., NR1H3 mRNA) of cells and tissue(s), or organs(s) (e.g., liver). In preventing disease, the target gene may be one which is required for initiation or maintenance of the disease or which has been identified as being associated with a higher risk of contracting the disease. In treating disease, the oligonucleotide can be brought into contact with the cells, tissue(s), or organ(s) (e.g., liver) exhibiting or responsible for mediating the disease. For example, an oligonucleotide (e.g., an RNAi oligonucleotide) substantially identical to all or part of a wild-type (i.e., native) or mutated gene associated with a disorder or condition associated with NR1H3 expression may be brought into contact with or introduced into a cell or tissue type of interest such as a hepatocyte or other liver cell.

In some embodiments, the target gene may be a target gene from any mammal, such as a human target. Any target gene may be silenced according to the method described herein.

Methods described herein typically involve administering to a subject an effective amount of an oligonucleotide herein (e.g., a RNAi oligonucleotide), that is, an amount that produces or generates a desirable therapeutic result. A therapeutically acceptable amount may be an amount that therapeutically treats a disease or disorder. The appropriate dosage for any one subject will depend on certain factors, including the subject's size, body surface area, age, the composition to be administered, the active ingredient(s) in the composition, time and route of administration, general health, and other drugs being administered concurrently.

In some embodiments, a subject is administered any one of the compositions herein (e.g., a composition comprising an RNAi oligonucleotide described herein) either enterally (e.g., orally, by gastric feeding tube, by duodenal feeding tube, via gastrostomy or rectally), parenterally (e.g., subcutaneous injection, intravenous injection or infusion, intra-arterial injection or infusion, intraosseous infusion, intramuscular injection, intracerebral injection, intracerebroventricular injection, intrathecal), topically (e.g., epicutaneous, inhalational, via eye drops, or through a mucous membrane), or by direct injection into a target organ (e.g., the liver of a subject). Typically, oligonucleotides herein are administered intravenously or subcutaneously.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide), or a pharmaceutical composition comprising the oligonucleotide, is administered alone or in combination. In some embodiments, the oligonucleotides herein are administered in combination concurrently, sequentially (in any order), or intermittently. For example, two oligonucleotides may be co-administered concurrently. Alternatively, one oligonucleotide may be administered and followed any amount of time later (e.g., one hour, one day, one week or one month) by the administration of a second oligonucleotide.

In some embodiments, an oligonucleotide herein (e.g., an RNAi oligonucleotide), or a pharmaceutical composition comprising the oligonucleotide, is administered in combination with one or more additional pharmacologically active substances. In some embodiments the additional pharmacologically active substances are selected from e.g., anti-diabetic agents, anti-obesity agents, appetite regulating agents, antihypertensive agents, agents.

In some embodiments, the subject to be treated is a human or non-human primate or other mammalian subject. Other exemplary subjects include domesticated animals such as dogs and cats; livestock such as horses, cattle, pigs, sheep, goats, and chickens; and animals such as mice, rats, guinea pigs, and hamsters.

Kits

In some embodiments, the disclosure provides a kit comprising an oligonucleotide herein (e.g., an RNAi oligonucleotide), and instructions for use. In some embodiments, the kit comprises an oligonucleotide herein, and a package insert containing instructions for use of the kit and/or any component thereof. In some embodiments, the kit comprises, in a suitable container, an oligonucleotide herein, one or more controls, and various buffers, reagents, enzymes and other standard ingredients well known in the art. In some embodiments, the container comprises at least one vial, well, test tube, flask, bottle, syringe, or other container means, into which the oligonucleotide is placed, and in some instances, suitably aliquoted. In some embodiments where an additional component is provided, the kit contains additional containers into which this component is placed. The kits can also include a means for containing the oligonucleotide and any other reagent in close confinement for commercial sale. Such containers may include injection or blow-molded plastic containers into which the desired vials are retained. Containers and/or kits can include labeling with instructions for use and/or warnings.

In some embodiments, a kit comprises an oligonucleotide herein (e.g., an RNAi oligonucleotide), and a pharmaceutically acceptable carrier, or a pharmaceutical composition comprising the oligonucleotide and instructions for treating or delaying progression of a disease, disorder or condition associated with NR1H3 expression in a subject in need thereof.

Definitions

As used herein, the term “antisense oligonucleotide” encompasses a nucleic acid-based molecule which has a sequence complementary to all or part of the target mRNA, in particular seed sequence thereby capable of forming a duplex with a mRNA. Thus, the term “antisense oligonucleotide”, as used herein, may be referred to as “complementary nucleic acid-based inhibitor”.

As used herein, “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

As used herein, “administer,” “administering,” “administration” and the like refers to providing a substance (e.g., an oligonucleotide) to a subject in a manner that is pharmacologically useful (e.g., to treat a disease, disorder, or condition in the subject).

As used herein, “attenuate,” “attenuating,” “attenuation” and the like refers to reducing or effectively halting. As a non-limiting example, one or more of the treatments herein may reduce or effectively halt the onset or progression of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus in a subject. This attenuation may be exemplified by, for example, a decrease in one or more aspects (e.g., symptoms, tissue characteristics, and cellular, inflammatory, or immunological activity, etc.) of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus, no detectable progression (worsening) of one or more aspects fatty liver disease, or systemic lupus erythematosus, or no detectable aspects of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or systemic lupus erythematosus in a subject when they might otherwise be expected.

As used herein, “complementary” refers to a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand) that permits the two nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to a pyrimidine nucleotide of an opposing nucleic acid may base pair together by forming hydrogen bonds with one another. In some embodiments, complementary nucleotides can base pair in the Watson-Crick manner or in any other manner that allows for the formation of stable duplexes. In some embodiments, two nucleic acids may have regions of multiple nucleotides that are complementary with each other to form regions of complementarity, as described herein.

As used herein, “deoxyribonucleotide” refers to a nucleotide having a hydrogen in place of a hydroxyl at the 2′ position of its pentose sugar when compared with a ribonucleotide. A modified deoxyribonucleotide is a deoxyribonucleotide having one or more modifications or substitutions of atoms other than at the 2′ position, including modifications or substitutions in or of the sugar, phosphate group or base.

As used herein, “double-stranded oligonucleotide” or “ds oligonucleotide” refers to an oligonucleotide that is substantially in a duplex form. In some embodiments, the complementary base-pairing of duplex region(s) of a double-stranded oligonucleotide is formed between antiparallel sequences of nucleotides of covalently separate nucleic acid strands. In some embodiments, complementary base-pairing of duplex region(s) of a double-stranded oligonucleotide is formed between antiparallel sequences of nucleotides of nucleic acid strands that are covalently linked. In some embodiments, complementary base-pairing of duplex region(s) of a double-stranded oligonucleotide is formed from single nucleic acid strand that is folded (e.g., via a hairpin) to provide complementary antiparallel sequences of nucleotides that base pair together. In some embodiments, a double-stranded oligonucleotide comprises two covalently separate nucleic acid strands that are fully duplexed with one another. However, in some embodiments, a double-stranded oligonucleotide comprises two covalently separate nucleic acid strands that are partially duplexed (e.g., having overhangs at one or both ends). In some embodiments, a double-stranded oligonucleotide comprises antiparallel sequence of nucleotides that are partially complementary, and thus, may have one or more mismatches, which may include internal mismatches or end mismatches.

As used herein, “duplex,” in reference to nucleic acids (e.g., oligonucleotides), refers to a structure formed through complementary base pairing of two antiparallel sequences of nucleotides.

As used herein, “excipient” refers to a non-therapeutic agent that may be included in a composition, for example, to provide or contribute to a desired consistency or stabilizing effect.

As used herein, “hepatocyte” or “hepatocytes” refers to cells of the parenchymal tissues of the liver. These cells make up about 70-85% of the liver's mass and manufacture serum albumin, FBN and the prothrombin group of clotting factors (except for Factors 3 and 4). Markers for hepatocyte lineage cells include, but are not limited to, transthyretin (Ttr), glutamine synthetase (Glul), hepatocyte nuclear factor 1a (Hnf1a) and hepatocyte nuclear factor 4a (Hnf4a). Markers for mature hepatocytes may include, but are not limited to, cytochrome P450 (Cyp3a11), fumarylacetoacetate hydrolase (Fah), glucose 6-phosphate (G6p), albumin (Alb) and OC2-2F8. See, e.g., Huch et al. NATURE (2013); 494: 247-50.

As used herein, a “hepatotoxic agent” refers to a chemical compound, virus or other substance that is itself toxic to the liver or can be processed to form a metabolite that is toxic to the liver. Hepatotoxic agents may include, but are not limited to, carbon tetrachloride (CCl₄), acetaminophen (paracetamol), vinyl chloride, arsenic, chloroform, nonsteroidal anti-inflammatory drugs (such as aspirin and phenylbutazone).

As used herein, the term “NR1H3” refers to the gene which encodes to the protein Liver X receptor alpha, or LXR-alpha. LXR-alpha is a nuclear receptor protein that is encoded by NR1H3 (nuclear receptor subfamily 1, group H, member 3). The term “NR1H3” is intended to refer to all isoforms unless stated otherwise.

As used herein, “labile linker” refers to a linker that can be cleaved (e.g., by acidic pH). A “fairly stable linker” refers to a linker that cannot be readily cleaved.

As used herein, “liver inflammation” or “hepatitis” refers to a physical condition in which the liver becomes swollen, dysfunctional and/or painful, especially as a result of injury or infection, as may be caused by exposure to a hepatotoxic agent. Symptoms may include jaundice (yellowing of the skin or eyes), fatigue, weakness, nausea, vomiting, appetite reduction and weight loss. Liver inflammation, if left untreated, may progress to fibrosis, cirrhosis, liver failure or liver cancer.

As used herein, “liver fibrosis” “Liver Fibrosis” or “fibrosis of the liver” refers to an excessive accumulation in the liver of extracellular matrix proteins, which could include collagens (I, III, and IV), FBN, undulin, elastin, laminin, hyaluronan and proteoglycans resulting from inflammation and liver cell death. Liver fibrosis, if left untreated, may progress to cirrhosis, liver failure or liver cancer.

As used herein, “loop” refers to an unpaired region of a nucleic acid (e.g., oligonucleotide) that is flanked by two antiparallel regions of the nucleic acid that are sufficiently complementary to one another, such that under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cell), the two antiparallel regions, which flank the unpaired region, hybridize to form a duplex (referred to as a “stem”).

As used herein, “Metabolic syndrome’ or “metabolic liver disease” refers to a disorder characterized by a cluster of associated medical conditions and associated pathologies including, but not limited to the following medical conditions: abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, liver fibrosis, and low levels of high-density lipoprotein (HDL) levels. As used herein, the term metabolic syndrome or metabolic liver disease may encompass a wide array of direct and indirect manifestations, diseases and pathologies associated with metabolic syndrome and metabolic liver disease, with an expanded list of conditions used throughout the document.

As used herein, “modified internucleotide linkage” refers to an internucleotide linkage having one or more chemical modifications when compared with a reference internucleotide linkage comprising a phosphodiester bond. In some embodiments, a modified nucleotide is a non-naturally occurring linkage. Typically, a modified internucleotide linkage confers one or more desirable properties to a nucleic acid in which the modified internucleotide linkage is present. For example, a modified internucleotide linkage may improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, bioactivity, reduced immunogenicity, etc.

As used herein, “modified nucleotide” refers to a nucleotide having one or more chemical modifications when compared with a corresponding reference nucleotide selected from: adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenine deoxyribonucleotide, guanine deoxyribonucleotide, cytosine deoxyribonucleotide and thymidine deoxyribonucleotide. In some embodiments, a modified nucleotide is a non-naturally occurring nucleotide. In some embodiments, a modified nucleotide has one or more chemical modification in its sugar, nucleobase and/or phosphate group. In some embodiments, a modified nucleotide has one or more chemical moieties conjugated to a corresponding reference nucleotide. Typically, a modified nucleotide confers one or more desirable properties to a nucleic acid in which the modified nucleotide is present. For example, a modified nucleotide may improve thermal stability, resistance to degradation, nuclease resistance, solubility, bioavailability, bioactivity, reduced immunogenicity, etc.

As used herein, “nicked tetraloop structure” refers to a structure of a RNAi oligonucleotide that is characterized by separate sense (passenger) and antisense (guide) strands, in which the sense strand has a region of complementarity with the antisense strand, and in which at least one of the strands, generally the sense strand, has a tetraloop configured to stabilize an adjacent stem region formed within the at least one strand.

As used herein, “oligonucleotide” refers to a short nucleic acid (e.g., less than about 100 nucleotides in length). An oligonucleotide may be single-stranded (ss) or double-stranded (ds). An oligonucleotide may or may not have duplex regions. As a set of non-limiting examples, an oligonucleotide may be, but is not limited to, a small interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), dicer substrate interfering RNA (DsiRNA), antisense oligonucleotide, short siRNA or ss siRNA. In some embodiments, a double-stranded (dsRNA) is an RNAi oligonucleotide.

As used herein, “overhang” refers to terminal non-base pairing nucleotide(s) resulting from one strand or region extending beyond the terminus of a complementary strand with which the one strand or region forms a duplex. In some embodiments, an overhang comprises one or more unpaired nucleotides extending from a duplex region at the 5′ terminus or 3′ terminus of an oligonucleotide. In certain embodiments, the overhang is a 3′- or 5′-overhang on the antisense strand or sense strand of an oligonucleotide.

As used herein, “phosphate analog” refers to a chemical moiety that mimics the electrostatic and/or steric properties of a phosphate group. In some embodiments, a phosphate analog is positioned at the 5′ terminal nucleotide of an oligonucleotide in place of a 5′-phosphate, which is often susceptible to enzymatic removal. In some embodiments, a 5′ phosphate analog contains a phosphatase-resistant linkage. Examples of phosphate analogs include, but are not limited to, 5′ phosphonates, such as 5′ methylene phosphonate (5′-MP) and 5′-(E)-vinylphosphonate (5′-VP). In some embodiments, an oligonucleotide has a phosphate analog at a 4′-carbon position of the sugar (referred to as a “4′-phosphate analog”) at a 5′-terminal nucleotide. An example of a 4′-phosphate analog is oxymethylphosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar moiety (e.g., at its 4′-carbon) or analog thereof. See, e.g., US Provisional Patent Application Nos. 62/383,207 (filed on 2 Sep. 2016) and 62/393,401 (filed on 12 Sep. 2016). Other modifications have been developed for the 5′ end of oligonucleotides (see, e.g., Intl. Patent Application No. WO 2011/133871; U.S. Pat. No. 8,927,513; and Prakash et al. NUCLEIC ACIDS RES. (2015); 43: 2993-3011).

As used herein, “reduced expression” of a gene (e.g., NR1H3) refers to a decrease in the amount or level of RNA transcript (e.g., NR1H3 mRNA) or protein encoded by the gene and/or a decrease in the amount or level of activity of the gene in a cell, a population of cells, a sample, or a subject, when compared to an appropriate reference (e.g., a reference cell, population of cells, sample or subject). For example, the act of contacting a cell with an oligonucleotide herein (e.g., an oligonucleotide comprising an antisense strand having a nucleotide sequence that is complementary to a nucleotide sequence comprising NR1H3 mRNA) may result in a decrease in the amount or level of NR1H3 mRNA, protein and/or activity (e.g., via degradation of NR1H3 mRNA by the RNAi pathway) when compared to a cell that is not treated with the oligonucleotide. Similarly, and as used herein, “reducing expression” refers to an act that results in reduced expression of a gene (e.g., NR1H3).

As used herein, “reduction of NR1H3 expression” refers to a decrease in the amount or level of NR1H3 mRNA, NR1H3 protein and/or NR1H3 activity in a cell, a population of cells, a sample or a subject when compared to an appropriate reference (e.g., a reference cell, population of cells, sample, or subject).

As used herein, “region of complementarity” refers to a sequence of nucleotides of a nucleic acid (e.g., an oligonucleotide) that is sufficiently complementary to an antiparallel sequence of nucleotides to permit hybridization between the two sequences of nucleotides under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cell, etc.). In some embodiments, an oligonucleotide herein comprises a targeting sequence having a region of complementary to a mRNA target sequence.

As used herein, “ribonucleotide” refers to a nucleotide having a ribose as its pentose sugar, which contains a hydroxyl group at its 2′ position. A modified ribonucleotide is a ribonucleotide having one or more modifications or substitutions of atoms other than at the 2′ position, including modifications or substitutions in or of the ribose, phosphate group or base.

As used herein, “RNAi oligonucleotide” refers to either (a) a double-stranded oligonucleotide having a sense strand (passenger) and antisense strand (guide), in which the antisense strand or part of the antisense strand is used by the Argonaute 2 (Ago2) endonuclease in the cleavage of a target mRNA (e.g., NR1H3 mRNA) or (b) a single-stranded oligonucleotide having a single antisense strand, where that antisense strand (or part of that antisense strand) is used by the Ago2 endonuclease in the cleavage of a target mRNA (e.g., NR1H3 mRNA).

As used herein, “strand” refers to a single, contiguous sequence of nucleotides linked together through internucleotide linkages (e.g., phosphodiester linkages or phosphorothioate linkages). In some embodiments, a strand has two free ends (e.g., a 5′ end and a 3′ end).

As used herein, “subject” means any mammal, including mice, rabbits, and humans. In one embodiment, the subject is a human or NHP. Moreover, “individual” or “patient” may be used interchangeably with “subject.”

As used herein, “synthetic” refers to a nucleic acid or other molecule that is artificially synthesized (e.g., using a machine (e.g., a solid-state nucleic acid synthesizer)) or that is otherwise not derived from a natural source (e.g., a cell or organism) that normally produces the molecule.

As used herein, “targeting ligand” refers to a molecule (e.g., a carbohydrate, amino sugar, cholesterol, polypeptide, or lipid) that selectively binds to a cognate molecule (e.g., a receptor) of a tissue or cell of interest and that is conjugatable to another substance for purposes of targeting the other substance to the tissue or cell of interest. For example, in some embodiments, a targeting ligand may be conjugated to an oligonucleotide for purposes of targeting the oligonucleotide to a specific tissue or cell of interest. In some embodiments, a targeting ligand selectively binds to a cell surface receptor. Accordingly, in some embodiments, a targeting ligand when conjugated to an oligonucleotide facilitates delivery of the oligonucleotide into a particular cell through selective binding to a receptor expressed on the surface of the cell and endosomal internalization by the cell of the complex comprising the oligonucleotide, targeting ligand and receptor. In some embodiments, a targeting ligand is conjugated to an oligonucleotide via a linker that is cleaved following or during cellular internalization such that the oligonucleotide is released from the targeting ligand in the cell. In some embodiments, the targeting ligand comprises at least one GalNAc moiety and targets the liver and human liver cells (e.g., human hepatocytes).

As used herein, “tetraloop” refers to a loop that increases stability of an adjacent duplex formed by hybridization of flanking sequences of nucleotides. The increase in stability is detectable as an increase in melting temperature (T_(m)) of an adjacent stem duplex that is higher than the T_(m) of the adjacent stem duplex expected, on average, from a set of loops of comparable length consisting of randomly selected sequences of nucleotides. For example, a tetraloop can confer a T_(m) of at least about 50° C., at least about 55° C., at least about 56° C., at least about 58° C., at least about 60° C., at least about 65° C., or at least about 75° C. in 10 mM Na₂HPO₄ to a hairpin comprising a duplex of at least 2 base pairs (bp) in length. In some embodiments, a tetraloop can confer a Tm of at least about 50° C., at least about 55° C., at least about 56° C., at least about 58° C., at least about 60° C., at least about 65° C., or at least about 75° C. in 10 mM NaH₂PO4 to a hairpin comprising a duplex of at least 2 base pairs (bp) in length. In some embodiments, a tetraloop may stabilize a bp in an adjacent stem duplex by stacking interactions. In addition, interactions among the nucleotides in a tetraloop include, but are not limited to, non-Watson-Crick base pairing, stacking interactions, hydrogen bonding and contact interactions (Cheong et al. NATURE (1990); 346: 680-82; and Heus & Pardi SCIENCE (1991); 253: 191-94). In some embodiments, a tetraloop comprises or consists of 3 to 6 nucleotides and is typically 4 to 5 nucleotides. In certain embodiments, a tetraloop comprises or consists of 3, 4, 5, or 6 nucleotides, which may or may not be modified (e.g., which may or may not be conjugated to a targeting moiety). In one embodiment, a tetraloop consists of 4 nucleotides. Any nucleotide may be used in the tetraloop and standard IUPAC-IUB symbols for such nucleotides may be used as described in Cornish-Bowden NUCLEIC ACIDS RES. (1985); 13: 3021-30. For example, the letter “N” may be used to mean that any base may be in that position, the letter “R” may be used to show that A (adenine) or G (guanine) may be in that position, and “B” may be used to show that C (cytosine), G (guanine), or T (thymine) may be in that position. Examples of tetraloops include the UNCG family of tetraloops (e.g., UUCG), the GNRA family of tetraloops (e.g., GAAA), and the CUUG tetraloop (Woese et al. PROC. NATL. ACAD. SCI. USA (1990); 87: 8467-71; Antao et al. NUCLEIC ACIDS RES. (1991); 19: 5901-05). Examples of DNA tetraloops include the d(GNNA) family of tetraloops (e.g., d(GTTA), the d(GNRA)) family of tetraloops, the d(GNAB) family of tetraloops, the d(CNNG) family of tetraloops, and the d(TNCG) family of tetraloops (e.g., d(TTCG)). See, e.g., Nakano et al. BIOCHEM. (2002); 41: 14281-92; Shinji et al. NIPPON KAGAKKAI KOEN YOKOSHU (2000); 78: 731. In some embodiments, the tetraloop is contained within a nicked tetraloop structure.

As used herein, “treat” or “treating” refers to the act of providing care to a subject in need thereof, for example, by administering a therapeutic agent (e.g., an oligonucleotide herein) to the subject, for purposes of improving the health and/or well-being of the subject with respect to an existing condition (e.g., a disease, disorder) or to prevent or decrease the likelihood of the occurrence of a condition. In some embodiments, treatment involves reducing the frequency or severity of at least one sign, symptom or contributing factor of a condition (e.g., disease, disorder) experienced by a subject.

EXAMPLES

While the disclosure has been described with reference to the specific embodiments set forth in the following Examples, it should be understood by those skilled in the art that various changes may be made, and equivalents may be substituted without departing from the true spirit and scope of the disclosure. Further, the following Examples are offered by way of illustration and are not intended to limit the scope of the disclosure in any manner. In addition, modifications may be made to adapt to a situation, material, composition of matter, process, process step or steps, to the objective, spirit, and scope of the disclosure. All such modifications are intended to be within the scope of the disclosure. Standard techniques well known in the art or the techniques specifically described below were utilized.

Example 1: Preparation of RNAi Oligonucleotides Oligonucleotide Synthesis and Purification

The oligonucleotides (RNAi oligonucleotides) described in the foregoing Examples are chemically synthesized using methods described herein. Generally, RNAi oligonucleotides are synthesized using solid phase oligonucleotide synthesis methods as described for 19-23mer siRNAs (see, e.g., Scaringe et al. NUCLEIC ACIDS RES. (1990); 18: 5433-41 and Usman et al. J. AM. CHEM. SOC. (1987); 109: 7845-45; see also, U.S. Pat. Nos. 5,804,683; 5,831,071; 5,998,203; 6,008,400; 6,111,086; 6,117,657; 6,353,098; 6,362,323; 6,437,117 and 6,469,158) in addition to using known phosphoramidite synthesis (see, e.g. Hughes and Ellington, COLD SPRING HARB. PERSPECT. BIOL. (2017); 9(1): a023812; Beaucage S. L., Caruthers M. H. Studies on Nucleotide Chemistry V.: Deoxynucleoside Phosphoramidites A New Class of Key Intermediates for Deoxypolynucleotide Synthesis, TETRAHEDRON LETT. (1981); 22: 1859-62. doi:10.1016/S0040-4039(01)90461-7). dsRNAi oligonucleotides having a 19mer core sequence were formatted into constructs having a 25mer sense strand and a 27mer antisense strand to allow for processing by the RNAi machinery. The 19mer core sequence is complementary to a region in the NR1H3 mRNA.

Individual RNA strands were synthesized and HPLC purified according to standard methods (Integrated DNA Technologies; Coralville, Iowa). For example, RNA oligonucleotides were synthesized using solid phase phosphoramidite chemistry, deprotected and desalted on NAP-5 columns (Amersham Pharmacia Biotech; Piscataway, N.J.) using standard techniques (Damha & Olgivie, METHODS MOL. BIOL. (1993); 20: 81-114; Wincott et al. NUCLEIC ACIDS RES. (1995); 23: 2677-84). The oligomers were purified using ion-exchange high performance liquid chromatography (IE-HPLC) on an Amersham Source 15Q column (1.0 cm×25 cm; Amersham Pharmacia Biotech) using a 15 min step-linear gradient. The gradient varied from 90:10 Buffers A:B to 52:48 Buffers A:B, where Buffer A is 100 mM Tris pH 8.5 and Buffer B is 100 mM Tris pH 8.5, 1 M NaCl. Samples were monitored at 260 nm and peaks corresponding to the full-length oligonucleotide species were collected, pooled, desalted on NAP-5 columns, and lyophilized.

The purity of each oligomer was determined by capillary electrophoresis (CE) on a Beckman PACE 5000 (Beckman Coulter, Inc.; Fullerton, Calif.). The CE capillaries have a 100 μm inner diameter and contain ssDNA 100R Gel (Beckman-Coulter). Typically, about 0.6 nmole of oligonucleotide was injected into a capillary, run in an electric field of 444 V/cm, and was detected by UV absorbance at 260 nm. Denaturing Tris-Borate-7 M-urea running buffer was purchased from Beckman-Coulter. Oligoribonucleotides were obtained that were at least 90% pure as assessed by CE for use in experiments described below. Compound identity was verified by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectroscopy on a Voyager DE™ Biospectometry Work Station (Applied Biosystems; Foster City, Calif.) following the manufacturer's recommended protocol. Relative molecular masses of all oligomers were obtained, often within 0.2% of expected molecular mass.

Preparation of Duplexes

Single strand RNA oligomers were resuspended (e.g., at 100 μM concentration) in duplex buffer consisting of 100 mM potassium acetate, 30 mM HEPES, pH 7.5. Complementary sense and antisense strands were mixed in equal molar amounts to yield a final solution of, for example, 50 μM duplex. Samples were heated to 100° C. for 5′ in RNA buffer (IDT) and were allowed to cool to room temperature before use. The RNAi oligonucleotides were stored at −20° C. Single strand RNA oligomers were stored lyophilized or in nuclease-free water at −80° C.

Example 2: Generation of NR1H3-Targeting Double Stranded RNAi Oligonucleotides

Identification of NR1H3 mRNA Target Sequences

Nuclear Receptor Subfamily 1 Group H Member 3 (NR1H3) is a protein that regulates macrophage function, lipid homeostasis, and inflammation. To generate RNAi oligonucleotide inhibitors of NR1H3 expression, a computer-based algorithm was used to computationally identify NR1H3 mRNA target sequences suitable for assaying inhibition of NR1H3 expression by the RNAi pathway. The algorithm provided RNAi oligonucleotide guide (antisense) strand sequences each having a region of complementarity to a suitable NR1H3 target sequence of human NR1H3 mRNA. Some of the guide strand sequences identified by the algorithm were also complementary to the corresponding NR1H3 target sequence of monkey and/or mouse NR1H3 mRNA. NR1H3 RNAi oligonucleotides comprising a region of complementarity to homologous NR1H3 mRNA target sequences with nucleotide sequence similarity are predicted to have the ability to target homologous NR1H3 mRNAs.

RNAi oligonucleotides (formatted as DsiRNA oligonucleotides) were generated as described in Example 1 for evaluation in vitro. Each DsiRNA was generated with the same modification pattern, and each with a unique guide strand having a region of complementarity to a NR1H3 target sequence identified by the algorithm. Modifications for the sense and anti-sense DsiRNA included the following (X— any nucleotide; m—2′-O-methyl modified nucleotide; r—ribosyl modified nucleotide):

Sense Strand:

rXmXrXmXrXrXrXrXrXrXrXrXrXmXrXmXrXrXrXrXrXrXrXXX

Anti-sense Strand:

mXmXmXmXrXrXrXrXrXrXmXrXmXrXrXrXrXrXrXrXrXrXmXrXmXmXmX

In Vitro Cell-Based Assays

The ability of each of the modified DsiRNA in Table 1 to reduce NR1H3 mRNA was measured using in vitro cell-based assays. Briefly, human Huh-7 cells expressing endogenous human NR1H3 gene were transfected with each of the DsiRNAs listed in Table 1 at 1 nM in separate wells of a multi-well cell-culture plate. Cells were maintained for 24 hours following transfection with the modified DsiRNA, and then the amount of remaining NR1H3 mRNA from the transfected cells was determined using and RT-qPCR assay. The assay used the following primers and probe normalized to the geometric mean of two reference genes HPRT1 and SFRS9: Forward-1198 GTTATAACCGGGAAGACTTTGC (SEQ ID NO:1122); Reverse-1326: TGATAGCAATGAGCAAGGCA (SEQ ID NO: 1123); Probe-1253: ATGGCCCTGGAGAACTCGAAGATG (SEQ ID NO:1124). The primer pair was assayed for % remaining RNA as shown in Table 1. DsiRNAs resulting in less than or equal to 10% NR1H3 mRNA remaining in DsiRNA-transfected cells when compared to mock-transfected cells were considered DsiRNA “hits”. The HuH-7 cell-based assay evaluating the ability of the DsiRNAs listed in Table 1 to inhibit NR1H3 expression identified several candidate DsiRNAs.

Taken together, these results show that DsiRNAs designed to target human NR1H3 mRNA inhibit NR1H3 expression in cells, as determined by a reduced amount of NR1H3 mRNA in DsiRNA-transfected cells relative to control cells. These results demonstrate that the nucleotide sequences comprising the DsiRNA are useful for generating RNAi oligonucleotides to inhibit NR1H3 expression. Further, these results demonstrate that multiple NR1H3 mRNA target sequences are suitable for the RNAi-mediated inhibition of NR1H3 expression.

TABLE 1 In Vitro Screening Results SED ID SED ID NO NO NR1H3-F1198 (Sense (Anti-sense % Strand) Strand) DsiRNA name remaining SEM 1 385 NR1H3-764-784-861 8.9 4.43 2 386 NR1H3-766-786-863 16.25 3.11 3 387 NR1H3-789-809-886 15.08 1.03 4 388 NR1H3-790-810-887 18.74 3.03 5 389 NR1H3-791-811-888 40.34 2.62 6 390 NR1H3-792-812-889 32.44 4.47 7 391 NR1H3-793-813-890 33.77 2.89 8 392 NR1H3-795-815-892 10.87 4.86 9 393 NR1H3-796-816-893 14.94 1.85 10 394 NR1H3-797-817-894 45.07 9.79 11 395 NR1H3-798-818-895 17.91 4.71 12 396 NR1H3-799-819-896 17.87 2.13 13 397 NR1H3-802-822-899 8.47 3.71 14 398 NR1H3-803-823-900 26.43 3.01 15 399 NR1H3-804-824-901 13.60 2.34 16 400 NR1H3-806-826-903 47.05 7.86 17 401 NR1H3-808-828-905 14.07 1.86 18 402 NR1H3-809-829-906 37.06 10.23 19 403 NR1H3-810-830-907 27.90 12.22 20 404 NR1H3-811-831-908 41.69 8.58 21 405 NR1H3-813-833-910 29.81 2.83 22 406 NR1H3-844 22.31 3.43 23 407 NR1H3-895-915-992 13.4 2.84 24 408 NR1H3-898-918-995 21.63 3.63 25 409 NR1H3-915-935 23.64 3.59 26 410 NR1H3-917-937 13.58 3.29 27 411 NR1H3-922-942 21.35 3.75 28 412 NR1H3-924-944 32.89 16.44 29 413 NR1H3-925-945 15.74 4.69 30 414 NR1H3-927-947 26.60 5.18 31 415 NR1H3-928-948 14.55 3.21 32 416 NR1H3-929-949 9.89 1.40 33 417 NR1H3-930-950 26.20 3.86 34 418 NR1H3-931-951 27.44 1.62 35 419 NR1H3-932-952 12.31 6.33 36 420 NR1H3-933-953 13.29 1.84 37 421 NR1H3-941-961 10.08 2.10 38 422 NR1H3-944-964 13.78 1.05 39 423 NR1H3-945-965 27.16 2.75 40 424 NR1H3-946-966 15.99 1.88 41 425 NR1H3-947-967 8.63 3.01 42 426 NR1H3-949-969 17.43 1.64 43 427 NR1H3-951-971 9.66 1.70 44 428 NR1H3-952-972 9.92 1.39 45 429 NR1H3-953-973 21.75 4.12 46 430 NR1H3-1151-1171 18.83 2.78 47 431 NR1H3-1153-1173 78.76 9.71 48 432 NR1H3-1154-1174 45.38 5.78 49 433 NR1H3-1155-1175 23.72 2.37 50 434 NR1H3-1156-1176 23.75 2.37 51 435 NR1H3-1157-1177 67.42 6.83 52 436 NR1H3-1158-1178 17.98 2.57 53 437 NR1H3-1159-1179 17.47 2.49 54 438 NR1H3-1160-1180 9.14 1.61 55 439 NR1H3-1161-1181 22.52 2.41 56 440 NR1H3-1162-1182 10.89 1.66 57 441 NR1H3-1163-1183 38.50 7.62 58 442 NR1H3-1164-1184 23.52 9.14 59 443 NR1H3-1165-1185 22.81 3.68 60 444 NR1H3-1166-1186 23.01 4.64 61 445 NR1H3-1167-1187 50.54 10.76 62 446 NR1H3-1169-1189 15.60 2.02 63 447 NR1H3-1170-1190 22.78 5.79 64 448 NR1H3-1171-1191 80.98 9.76 65 449 NR1H3-1173-1193 16.14 4.16 66 450 NR1H3-1175-1195 45.81 7.47 67 451 NR1H3-1176-1196 18.32 4.59 68 452 NR1H3-1177-1197 26.85 5.22 69 453 NR1H3-1178-1198 63.10 17.52 70 454 NR1H3-1179-1199 12.86 1.65 71 455 NR1H3-1180-1200 20.97 4.62 72 456 NR1H3-1181-1201 16.21 4.23 73 457 NR1H3-1182-1202 30.61 5.64 74 458 NR1H3-1183-1203 30.96 6.72 75 459 NR1H3-1184-1204 23.71 6.05 76 460 NR1H3-1185-1205 14.77 1.30 77 461 NR1H3-1186-1206 19.94 6.28 78 462 NR1H3-1187-1207 14.48 1.77 79 463 NR1H3-1188-1208 37.28 3.76 80 464 NR1H3-1190-1210 38.58 4.63 81 465 NR1H3-1191-1211 15.02 2.19 82 466 NR1H3-1192-1212 51.23 7.43 83 467 NR1H3-1193-1213 17.05 3.23 84 468 NR1H3-1194-1214 31.91 6.24 85 469 NR1H3-1196-1216 32.00 9.03 86 470 NR1H3-1197-1217 8.36 2.55 87 471 NR1H3-1198-1218 29.10 4.48 88 472 NR1H3-1199-1219 13.22 2.89 89 473 NR1H3-1200-1220 8.59 2.38 90 474 NR1H3-1203-1223 15.92 3.29 91 475 NR1H3-1204-1224 5.07 0.83 92 476 NR1H3-1207-1227 3.54 2.18 93 477 NR1H3-1211-1231 1.88 1.19 94 478 NR1H3-1212-1232 17.48 7.55 95 479 NR1H3-1213-1233 8.32 4.17 96 480 NR1H3-1214-1234 16.53 1.70 97 481 NR1H3-1215-1235 11.84 1.93 98 482 NR1H3-1216-1236 9.48 1.67 99 483 NR1H3-1217-1237 11.9 2.34 100 484 NR1H3-1218-1238 8.45 1.98 101 485 NR1H3-1219-1239 6.80 1.35 102 486 NR1H3-1220-1240 3.60 1.88 103 487 NR1H3-1222-1242 8.53 1.67 104 488 NR1H3-1223-1243 12.69 1.63 105 489 NR1H3-1224-1244 6.15 2.42 106 490 NR1H3-1225-1245 9.72 3.87 107 491 NR1H3-1226-1246 47.24 5.54 108 492 NR1H3-1227-1247 13.80 2.63 109 493 NR1H3-1228-1248 6.76 1.78 110 494 NR1H3-1229-1249 8.75 2.71 111 495 NR1H3-1232-1252 36.21 3.20 112 496 NR1H3-1233-1253 20.37 2.75 113 497 NR1H3-1234-1254 18.42 1.50 114 498 NR1H3-1235-1255 16.37 1.48 115 499 NR1H3-1236-1256 58.83 6.78 116 500 NR1H3-1237-1257 16.03 2.29 117 501 NR1H3-1238-1258 19.29 5.59 118 502 NR1H3-1241-1261 12.44 2.25 119 503 NR1H3-1242-1262 29.53 10.05 120 504 NR1H3-1243-1263 6.22 5.33 121 505 NR1H3-1244-1264 5.51 0.94 122 506 NR1H3-1245-1265 15.00 2.82 123 507 NR1H3-1246-1266 10.14 2.84 124 508 NR1H3-1247-1267 13.70 3.55 125 509 NR1H3-1248-1268 37.81 4.12 126 510 NR1H3-1250-1270 10.08 2.10 127 511 NR1H3-1251-1271 6.50 0.47 128 512 NR1H3-1252-1272 3.35 0.65 129 513 NR1H3-1253-1273 14.22 1.35 130 514 NR1H3-1256-1276 8.26 1.63 131 515 NR1H3-1258-1278 7.38 1.26 132 516 NR1H3-1259-1279 4.72 1.13 133 517 NR1H3-1261-1281 4.39 1.31 134 518 NR1H3-1262-1282 27.66 5.46 135 519 NR1H3-1265-1285 3.35 1.10 136 520 NR1H3-1266-1286 4.91 0.83 137 521 NR1H3-1267-1287 21.91 4.48 138 522 NR1H3-1268-1288 21.59 3.96 139 523 NR1H3-1269-1289 11.31 1.44 140 524 NR1H3-1270-1290 9.87 5.24 141 525 NR1H3-1271-1291 6.95 1.9 142 526 NR1H3-1272-1292 7.07 0.99 143 527 NR1H3-1273-1293 11.01 3.72 144 528 NR1H3-1275-1295 18.49 2.31 145 529 NR1H3-1276-1296 17.77 3.25 146 530 NR1H3-1277-1297 18.20 1.62 147 531 NR1H3-1278-1298 9.35 1.70 148 532 NR1H3-1279-1299 8.96 1.60 149 533 NR1H3-1280-1300 19.16 3.95 150 534 NR1H3-1281-1301 12.33 1.94 151 535 NR1H3-1282-1302 40.52 7.51 152 536 NR1H3-1283-1303 15.26 7.23 153 537 NR1H3-1284-1304 37.09 9.79 154 538 NR1H3-1285-1305 29.28 4.88 155 539 NR1H3-1286-1306 41.56 4.92 156 540 NR1H3-1288-1308 68.84 4.13 157 541 NR1H3-1289-1309 34.44 10.86 158 542 NR1H3-1290-1310 17.67 3.83 159 543 NR1H3-1291-1311 21.47 2.26 160 544 NR1H3-1292-1312 41.99 7.72 161 545 NR1H3-1293-1313 13.77 1.40 162 546 NR1H3-1294-1314 20.97 3.76 163 547 NR1H3-1295-1315 14.39 3.21 164 548 NR1H3-1296-1316 28.04 10.25 165 549 NR1H3-1297-1317 12.70 2.20 166 550 NR1H3-1338-1358 22.20 4.81 167 551 NR1H3-1339-1359 7.86 1.5 168 552 NR1H3-1340-1360 4.72 1.10 169 553 NR1H3-1341-1361 11.49 4.26 170 554 NR1H3-1342-1362 4.84 1.18 171 555 NR1H3-1343-1363 17.05 4.21 172 556 NR1H3-1344-1364 13.83 6.27 173 557 NR1H3-1345-1365 9.55 1.22 174 558 NR1H3-1346-1366 4.54 1.14 175 559 NR1H3-1347-1367 6.47 1.87 176 560 NR1H3-1377-1443 46.13 5.08 177 561 NR1H3-1379-1445 28.21 2.69 178 562 NR1H3-1383-1449 27.33 3.23 179 563 NR1H3-1384-1450 27.81 4.58 180 564 NR1H3-1385-1451 44.36 4.37 181 565 NR1H3-1387-1453 15.50 2.5 182 566 NR1H3-1388-1454 46.03 6.42 183 567 NR1H3-1391-1457 20.33 2.82 184 568 NR1H3-1393-1459 27.25 2.95 185 569 NR1H3-1394-1460 11.31 2.71 186 570 NR1H3-1395-1461 30.82 3.24 187 571 NR1H3-1396-1462 34.98 4.45 188 572 NR1H3-1397-1463 41.12 4.28 189 573 NR1H3-1398-1464 14.14 2.79 190 574 NR1H3-1399-1465 14.46 2.61 191 575 NR1H3-1400-1466 49.48 5.89 192 576 NR1H3-1401-1467 21.19 3.39 193 577 NR1H3-1402-1468 14.17 2.73 194 578 NR1H3-1403-1469 18.25 1.29 195 579 NR1H3-1404-1470 34.21 2.29 196 580 NR1H3-1406-1472 46.79 7.22 197 581 NR1H3-1407-1473 13.59 2.47 198 582 NR1H3-1408-1474 44.63 5.37 199 583 NR1H3-1410-1476 43.93 9.37 200 584 NR1H3-1411-1477 28.12 4.11 201 585 NR1H3-1412-1478 50.22 11.35 202 586 NR1H3-1413-1479 45.56 6.23 203 587 NR1H3-1414-1480 56.42 9.61 204 588 NR1H3-1415-1481 32.43 10.32 205 589 NR1H3-1416-1482 16.66 2.27 206 590 NR1H3-1417-1483 31.84 4.71 207 591 NR1H3-1418-1484 7.07 0.80 208 592 NR1H3-1419-1485 69.83 8.81 209 593 NR1H3-1420-1486 16.01 5.34 210 594 NR1H3-1421-1487 38.29 6.31 211 595 NR1H3-1422-1488 80.48 13.59 212 596 NR1H3-1423-1489 9.79 1.47 213 597 NR1H3-1424-1490 9.36 1.84 214 598 NR1H3-1425-1491 22.14 3.77 215 599 NR1H3-1426-1492 9.86 2.14 216 600 NR1H3-1427-1493 18.88 6.80 217 601 NR1H3-1428-1494 17.55 5.52 218 602 NR1H3-1429-1495 2.77 1.08 219 603 NR1H3-1430-1496 19.29 3.14 220 604 NR1H3-1431-1497 8.66 3.71 221 605 NR1H3-1432-1498 19.76 3.07 222 606 NR1H3-1433-1499 3.37 2.29 223 607 NR1H3-1434-1500 77.93 11.83 224 608 NR1H3-1435-1501 14.53 5.77 225 609 NR1H3-1436-1502 11.42 2.45 226 610 NR1H3-1437-1503 4.97 1.57 227 611 NR1H3-1438-1504 7.40 1.89 228 612 NR1H3-1439-1505 3.26 0.97 229 613 NR1H3-1440-1506 40.21 5.31 230 614 NR1H3-1442-1508 50.09 3.47 231 615 NR1H3-1443-1509 11.50 5.54 232 616 NR1H3-1444-1510 29.36 15.66 233 617 NR1H3-1445-1511 47.59 6.76 234 618 NR1H3-1446-1512 2.37 0.65 235 619 NR1H3-1447-1513 10.29 4.95 236 620 NR1H3-1448-1514 45.74 4.52 237 621 NR1H3-1449-1515 35.27 4.39 238 622 NR1H3-1450-1516 39.10 5.63 239 623 NR1H3-1451-1517 9.58 2.83 240 624 NR1H3-1452-1518 64.45 15.14 241 625 NR1H3-1453-1519 14.78 2.76 242 626 NR1H3-1454-1520 5.01 2.14 243 627 NR1H3-1455-1521 21.75 3.59 244 628 NR1H3-1456-1522 9.11 2.01 245 629 NR1H3-1457-1523 7.52 3.29 246 630 NR1H3-1459-1525 7.81 1.75 247 631 NR1H3-1460-1526 4.57 1.07 248 632 NR1H3-1461-1527 30.77 4.42 249 633 NR1H3-1462-1528 6.29 1.92 250 634 NR1H3-1463-1529 2.58 0.85 251 635 NR1H3-1465-1531 4.17 1.14 252 636 NR1H3-1466-1532 15.04 1.90 253 637 NR1H3-1468-1534 14.47 1.37 254 638 NR1H3-1469-1535 14.04 2.26 255 639 NR1H3-1471-1537 14.94 1.55 256 640 NR1H3-1472-1538 45.97 3.01 257 641 NR1H3-1473-1539 19.37 8.93 258 642 NR1H3-1474-1540 9.53 2.70 259 643 NR1H3-1475-1541 3.21 1.94 260 644 NR1H3-1476-1542 11.27 4.12 261 645 NR1H3-1477-1543 14.30 2.78 262 646 NR1H3-1478-1544 13.06 3.66 263 647 NR1H3-1479-1545 3.97 0.86 264 648 NR1H3-1480-1546 4.82 1.41 265 649 NR1H3-1481-1547 2.81 0.57 266 650 NR1H3-1483-1549 5.56 1.60 267 651 NR1H3-1484-1550 20.18 2.39 268 652 NR1H3-1485-1551 3.52 2.10 269 653 NR1H3-1486-1552 13.41 1.81 270 654 NR1H3-1487-1553 25.35 3.42 271 655 NR1H3-1488-1554 28.45 6.63 272 656 NR1H3-1489-1555 15.31 5.00 273 657 NR1H3-1491-1557 6.33 1.03 274 658 NR1H3-1492-1558 20.75 4.42 275 659 NR1H3-1494-1560 24.97 4.76 276 660 NR1H3-1505-1571 38.74 5.88 277 661 NR1H3-1507-1573 9.42 2.29 278 662 NR1H3-1508-1574 36.57 6.54 279 663 NR1H3-1509-1575 29.82 5.45 280 664 NR1H3-1510-1576 19.45 3.79 281 665 NR1H3-1511-1577 23.73 3.3 282 666 NR1H3-1512-1578 42.41 7.68 283 667 NR1H3-1513-1579 33.80 5.58 284 668 NR1H3-1514-1580 26.85 4.79 285 669 NR1H3-1515-1581 3.95 0.84 286 670 NR1H3-1516-1582 16.48 3.36 287 671 NR1H3-1517-1583 4.38 1.57 288 672 NR1H3-1518-1584 3.43 1.32 289 673 NR1H3-1519-1585 5.73 1.72 290 674 NR1H3-1520-1586 14.37 1.95 291 675 NR1H3-1521-1587 15.60 9.44 292 676 NR1H3-1522-1588 14.40 3.9 293 677 NR1H3-1523-1589 9.60 2.11 294 678 NR1H3-1525-1591 13.51 4.15 295 679 NR1H3-1526-1592 50.59 16.74 296 680 NR1H3-1527-1593 8.47 4.27 297 681 NR1H3-1528-1594 25.44 3.59 298 682 NR1H3-1529-1595 12.55 2.77 299 683 NR1H3-1530-1596 11.6 3.15 300 684 NR1H3-1531-1597 6.14 2.83 301 685 NR1H3-1532-1598 15.35 4.55 302 686 NR1H3-1533-1599 3.13 3 303 687 NR1H3-1534-1600 8.51 3.07 304 688 NR1H3-1535-1601 1.48 0.67 305 689 NR1H3-1536-1602 30.02 10.69 306 690 NR1H3-1537-1603 17.55 6.31 307 691 NR1H3-1538-1604 21.90 1.81 308 692 NR1H3-1539-1605 28.62 6.45 309 693 NR1H3-1540-1606 19.29 5.08 310 694 NR1H3-1541-1607 10.51 2.94 311 695 NR1H3-1542-1608 8.39 6.98 312 696 NR1H3-1543-1609 5.68 3.86 313 697 NR1H3-1544-1610 23.78 4.02 314 698 NR1H3-1545-1611 3.93 1.19 315 699 NR1H3-1546-1612 11.55 1.89 316 700 NR1H3-1547-1613 16.77 3.13 317 701 NR1H3-1548-1614 10.86 7.45 318 702 NR1H3-1549-1615 33.40 8.27 319 703 NR1H3-1550-1616 13.98 3.23 320 704 NR1H3-1551-1617 32.11 9.43 321 705 NR1H3-1553-1619 43.83 11.06 322 706 NR1H3-1554-1620 5.16 1.29 323 707 NR1H3-1555-1621 89.05 22.10 324 708 NR1H3-1556-1622 33.15 4.79 325 709 NR1H3-1558-1624 15.27 4.11 326 710 NR1H3-1559-1625 15.15 3.47 327 711 NR1H3-1560-1626 34.65 4.83 328 712 NR1H3-1561-1627 63.67 7.04 329 713 NR1H3-1562-1628 16.78 10.54 330 714 NR1H3-1563-1629 26.54 9.20 331 715 NR1H3-1564-1630 34.34 14.27 332 716 NR1H3-1565-1631 89.42 16.51 333 717 NR1H3-1567-1633 66.56 5.80 334 718 NR1H3-1569-1635 39.41 11.96 335 719 NR1H3-1570-1636 25.11 4.45 336 720 NR1H3-1572-1638 24.43 4.3 337 721 NR1H3-1573-1639 13.36 2.16 338 722 NR1H3-1574-1640 82.95 11.20 339 723 NR1H3-1577-1643 35.42 6.60 340 724 NR1H3-1579-1645 18.88 2.81 341 725 NR1H3-1580-1646 21.56 5.67 342 726 NR1H3-1581-1647 4.90 1.52 343 727 NR1H3-1582-1648 10.89 3.83 344 728 NR1H3-1583-1649 13.79 6.45 345 729 NR1H3-1584-1650 16.62 7.10 346 730 NR1H3-1585-1651 5.99 2.91 347 731 NR1H3-1586-1652 3.86 0.94 348 732 NR1H3-1587-1653 4.72 0.90 349 733 NR1H3-1588-1654 2.35 0.39 350 734 NR1H3-1589-1655 47.09 6.4 351 735 NR1H3-1590-1656 12.18 2.49 352 736 NR1H3-1591-1657 7.90 3.08 353 737 NR1H3-1592-1658 13.57 3.13 354 738 NR1H3-1593-1659 31.19 18.86 355 739 NR1H3-1656-1720 31.57 13.68 356 740 NR1H3-1657-1721 21.24 4.73 357 741 NR1H3-1658-1722 15.81 4.89 358 742 NR1H3-1659-1723 12.33 4.79 359 743 NR1H3-1660-1724 22.98 7.43 360 744 NR1H3-1661-1725 9.37 3.58 361 745 NR1H3-1662-1726 8.29 2.01 362 746 NR1H3-1663-1727 4.60 1.56 363 747 NR1H3-1664-1728 16.48 1.97 364 748 NR1H3-1665-1729 17.41 2.6 365 749 NR1H3-1666-1730 23.86 4.49 366 750 NR1H3-1667-1731 23.67 5.80 367 751 NR1H3-1668-1732 27.34 4.76 368 752 NR1H3-1669-1733 9.25 2.46 369 753 NR1H3-1671-1735 5.99 1.88 370 754 NR1H3-1677-1741 28.16 4.53 371 755 NR1H3-1679-1743 10.30 2.96 372 756 NR1H3-1680-1744 13.50 3.80 373 757 NR1H3-1681-1745 12.10 2.74 374 758 NR1H3-1682-1746 17.59 5.47 375 759 NR1H3-1683-1747 17.57 14.50 376 760 NR1H3-1684-1748 3.97 0.47 377 761 NR1H3-1685-1749 7.55 2.88 378 762 NR1H3-1686-1750 8.97 4.18 379 763 NR1H3-1687-1751 16.24 8.75 380 764 NR1H3-1728-1792 6.44 1.49 381 765 NR1H3-1729-1793 8.96 3.52 382 766 NR1H3-1730-1794 15.41 8.06 383 767 NR1H3-1731-1795 5.40 2.04 384 768 NR1H3-1732-1796 3.85 0.85

Example 3: GalNAc-Conjugated NR1H3 RNAi Oligonucleotides Inhibit Human NR1H3 in Vitro

The in vitro screening assay in Example 2 validated the ability of NR1H3-targeting DsiRNA to knockdown NR1H3 mRNA. To further evaluate the ability of NR1H3 RNAi oligonucleotides to inhibit NR1H3 mRNA expression, GalNAc-conjugated NR1H3 oligonucleotides were generated using sequences identified by the algorithm in Example 2.

Specifically, a subset of the DsiRNAs identified by the algorithm were used to generate corresponding double-stranded RNAi oligonucleotides comprising a nicked tetraloop GalNAc-conjugated structure (referred to herein as “GalNAc-conjugated NR1H3 oligonucleotides” or “GalNAc-NR1H3 constructs”) having a 36-mer passenger strand and a 22-mer guide strand (Table 3). Further, two nucleotide sequences comprising the passenger strand and guide strand have a distinct pattern of modified nucleotides and phosphorothioate linkages (sense strand SEQ ID Nos: 945-1032; antisense SEQ ID Nos:1037 and 1086). Three of the nucleotides comprising the tetraloop were each conjugated to a GalNAc moiety (CAS #14131-60-3). The modification pattern of each strand is illustrated below:

Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX[-mX-]16-[ademX-GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-mX-mX-3′.

Hybridized to: Antisense Strand: 5′-[MePhosphonate-40-mX]-S-fX-S-fX-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′.

(Modification key: Table 2 and [ademX-GalNAc]=GalNAc-conjugated nucleotide) Or, represented as:

Sense Strand: [mXs][mX][mX][mX][mX][mX][mX][fX][fX][fX][fX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mX][mX][mX][mX][mX][mX]

Hybridized to:

Antisense Strand: [MePhosphonate-4O-mXs][fXs][fX][fX][fX][mX][fX][mX][mX][fX][mX][mX][mX][fX][mX][mX][mX][mX][mX][mXs][mXs][mX]

The remainder of the nucleotide sequences comprising the passenger strand and guide strand have a second distinct pattern of modified nucleotides and phosphorothioate linkages (sense strand SEQ ID Nos: 945-1032; antisense SEQ ID NOs: 1033-1036, 1038-1085 and 1087-1120). Three of the nucleotides comprising the tetraloop were each conjugated to a GalNAc moiety (CAS #14131-60-3). The modification pattern of each strand is illustrated below: Sense Strand: 5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX[-mX-]16-[ademX-GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-mX-mX-3′.

Hybridized to: Antisense Strand: 5′-[MePhosphonate-40-mX]-S-fX-S-fX-S-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′.

(Modification key: Table 2 and [ademX-GalNAc]=GalNAc-conjugated nucleotide) Or, represented as:

Sense Strand: [mXs][mX][mX][mX][mX][mX][mX][fX][fX][fX][fX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][mX][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mX][mX][mX][mX][mX][mX]

Hybridized to:

Antisense Strand: [MePhosphonate-40-mXs][fXs][fXs][fX][fX][mX][fX][mX][mX][fX][mX][mX][mX][fX][mX][mX][mX][mX][mX][mXs][mXs][mX]

(Modification key: Table 2). Symbol Modification/linkage Key 1 mX 2′-O-methyl modified nucleotide fX 2'-fluoro modified nucleotide -S- phosphorothioate linkage - phosphodiester linkage [MePhosphonate-4O-mX] 5′-methoxyphosphonate-4′-oxy modified nucleotide ademA-GalNAc GalNAc attached to an adenine nucleotide Key 2 [mXs] 2′-O-methyl modified nucleotide with a phosphorothioate linkage to the neighboring nucleotide [fXs] 2′-fluoro modified nucleotide with a phosphorothioate linkage to the neighboring nucleotide [mX] 2′-O-methyl modified nucleotide with phosphodiester linkages to neighboring nucleotides [fX] 2′-fluoro modified nucleotide with phosphodiester linkages to neighboring nucleotides

GalNAc-NR1H3 constructs were used to evaluate inhibition efficacy in cells expressing human NR1H3. Specifically, Huh-7 cells were transfected with the GalNAc-NR1H3 constructs using methods described in Example 2. Results are provided in Table 3, which demonstrate successful knock-down of human NR1H3 mRNA with several constructs.

TABLE 3 GalNAc-Conjugated Human NR1H3 RNAi Oligonucleotides SED ID SED ID NO NO (modified (modified Anti- Sense sense % Strand) Strand) DsiRNA name remaining SEM 945 1033 NR1H3-763-783-860 109.29 17.94 946 1034 NR1H3-765-785-862 57.30 15.34 947 1035 NR1H3-767-787-864 31.55 7.72 948 1036 NR1H3-768-788-865 89.93 18.03 949 1037 NR1H3-769-789-866 18.84 4.39 950 1038 NR1H3-794-814-891 40.26 12.66 951 1039 NR1H3-1152-1172-1249 74.17 12.97 952 1040 NR1H3-1189-1209-1286 47.09 11.14 953 1041 NR1H3-1195-1215-1292 41.72 9.81 954 1042 NR1H3-1200-1220-1297 102.50 25.27 955 1043 NR1H3-1201-1221-1298 28.78 4.63 956 1044 NR1H3-1202-1222-1299 16.81 5.40 957 1045 NR1H3-1203-1223-1300 11.40 3.12 958 1046 NR1H3-1204-1224-1301 10.27 9.33 959 1047 NR1H3-1205-1225-1302 15.93 5.10 960 1048 NR1H3-1206-1226-1303 59.82 14.86 962 1050 NR1H3-1208-1228-1305 10.94 1.83 963 1051 NR1H3-1209-1229-1306 101.62 23.09 964 1052 NR1H3-1210-1230-1307 25.85 6.52 965 1053 NR1H3-1211-1231-1308 29.68 4.19 966 1054 NR1H3-1212-1232-1309 39.90 13.07 967 1055 NR1H3-1213-1233-1310 15.16 4.91 968 1056 NR1H3-1214-1234-1311 25.26 16.03 970 1058 NR1H3-1221-1241-1318 23.77 6.65 973 1061 NR1H3-1249-1269-1346 45.75 8.54 975 1063 NR1H3-1254-1274-1351 36.79 10.59 976 1064 NR1H3-1255-1275-1352 16.79 4.54 977 1065 NR1H3-1256-1276-1353 55.93 16.15 978 1066 NR1H3-1257-1277-1354 90.17 15.01 980 1068 NR1H3-1260-1280-1357 17.80 2.89 981 1069 NR1H3-1261-1281-1358 81.65 24.27 982 1070 NR1H3-1263-1283-1360 15.12 5.37 983 1071 NR1H3-1264-1284-1361 25.69 6.43 986 1074 NR1H3-1405-1471-1502 40.51 10.03 987 1075 NR1H3-1409-1475-1506 43.45 7.797 993 1081 NR1H3-1458-1524-1555 6.54 1.345 995 1083 NR1H3-1464-1530-1561 53.64 10.29 996 1084 NR1H3-1465-1531-1562 33.78 10.83 997 1085 NR1H3-1467-1533-1564 33.29 19.93 998 1086 NR1H3-1469-1535-1566 20.17 7.60 999 1087 NR1H3-1470-1536-1567 34.02 6.95 1002 1088 NR1H3-1480-1546-1577 31.73 6.53 1004 1092 NR1H3-1482-1548-1579 12.18 3.56 1009 1097 NR1H3-1524-1590-1621 28.36 10.49 1018 1106 NR1H3-1594-1660-1691 30.67 13.85 1019 1107 NR1H3-1595-1661-1692 50.80 8.90 1020 1108 NR1H3-1596-1662 56.02 19.49 1022 1110 NR1H3-1670-1734 10.71 5.09 1024 1112 NR1H3-1672-1736 25.94 11.33 1025 1113 NR1H3-1673-1737 53.70 17.23 1026 1114 NR1H3-1674-1738 14.48 2.82 1027 1115 NR1H3-1675-1739-1766 55.04 10.59 1028 1116 NR1H3-1676-1740-1767 33.47 12.90 1029 1117 NR1H3-1678-1742-1769 364.22 31.30

Example 4: RNAi Oligonucleotide Inhibition of NR1H3 Expression in Mice In Vivo

The in vitro screening assays in Examples 2 and 3 validated the ability of NR1H3-targeting oligonucleotides to knock-down target mRNA. To confirm the ability of the RNAi oligonucleotides to knockdown NR1H3 in vivo, an HDI mouse model was used. Two sets of GalNAc-conjugated NR1H3 oligonucleotides were evaluated. Specifically, a set of GalNAc-conjugated NR1H3 oligonucleotides were generated from DsiRNA screened in Example 2 (as shown in Table 4) and the GalNAc-conjugated NR1H3 oligonucleotides from Example 3 (as shown in Table 5). Both sets of constructs were evaluated in mice engineered to transiently express human NR1H3 mRNA in hepatocytes of the mouse liver. Briefly, 6-8-week-old female CD-1 mice (n=4-5) were subcutaneously administered the indicated GalNAc-conjugated NR1H3 oligonucleotides at a dose of 2 mg/kg formulated in PBS. A control group of mice (n=5) were administered only PBS. Three days later (72 hours), the mice were hydrodynamically injected (HDI) with a DNA plasmid encoding the full human NR1H3 gene (25 μg) under control of a ubiquitous cytomegalovirus (CMV) promoter sequence. One day after introduction of the DNA plasmid, liver samples from HDI mice were collected. Total RNA derived from these HDI mice were subjected to qRT-PCR analysis to determine NR1H3 mRNA levels as described in Example 2. mRNA levels were measured for both human and mouse mRNA. The values were normalized for transfection efficiency using the NeoR gene included on the DNA plasmid.

TABLE 4 GalNAc-Conjugated Human NR1H3 RNAi Oligonucleotides for HDI screen Unmodified Unmodified Modified Modified Sense Strand Antisense Sense Strand Antisense (SED ID strand (SED ID strand NO) (SED ID NO) NO) (SED ID NO) NR1H3-1207- 823 911 961 1049 1227 NR1H3-1220- 824 912 969 1057 1240 NR1H3-1224- 825 913 971 1059 1244 NR1H3-1244- 826 914 972 1060 1264 NR1H3-1252- 827 915 974 1062 1272 NR1H3-1259- 828 916 979 1067 1279 NR1H3-1265- 829 917 984 1072 1285 NR1H3-1266- 830 918 985 1073 1286 NR1H3-1429- 831 919 988 1076 1495 NR1H3-1433- 832 920 989 1077 1499 NR1H3-1437- 833 921 990 1078 1503 NR1H3-1439- 834 922 991 1079 1505 NR1H3-1446- 835 923 992 1080 1512 NR1H3-1463- 836 924 994 1082 1529 NR1H3-1475- 837 925 1000 1088 1541 NR1H3-1479- 838 926 1001 1089 1545 NR1H3-1481- 839 927 1003 1091 1547 NR1H3-1485- 840 928 1005 1093 1551 NR1H3-1515- 1537 929 1006 1094 1581 NR1H3-1517- 842 930 1007 1095 1583 NR1H3-1518- 843 931 1008 1096 1584 NR1H3-1533- 844 932 1010 1098 1599 NR1H3-1535- 845 933 1011 1099 1601 NR1H3-1545- 846 934 1012 1100 1611 NR1H3-1554- 847 935 1013 1101 1620 NR1H3-1581- 848 936 1014 1102 1647 NR1H3-1586- 849 937 1015 1103 1652 NR1H3-1587- 850 938 1016 1104 1653 NR1H3-1588- 851 939 1017 1105 1654 NR1H3-1663- 852 940 1021 1109 1727 NR1H3-1671- 853 941 1023 1111 1735 NR1H3-1684- 854 942 1030 1118 1748 NR1H3-1731- 855 943 1031 1119 1795 NR1H3-1732- 856 944 1032 1120 1796

TABLE 5 GalNAc-Conjugated Human NR1H3 RNAi Oligonucleotides for HDI screen Unmodified Unmodified Modified Modified Sense Strand Antisense Sense Strand Antisense (SED ID strand (SED ID strand NO) (SED ID NO) NO) (SED ID NO) NR1H3-763- 769 857 945 1033 783-860 NR1H3-765- 770 858 946 1034 785-862 NR1H3-767- 771 859 947 1035 787-864 NR1H3-768- 772 860 948 1036 788-865 NR1H3-769- 773 861 949 1037 789-866 NR1H3-794- 774 862 950 1038 814-891 NR1H3-1152- 775 863 951 1039 1172-1249 NR1H3-1189- 776 864 952 1040 1209-1286 NR1H3-1195- 777 865 953 1041 1215-1292 NR1H3-1200- 778 866 954 1042 1220-1297 NR1H3-1201- 779 867 955 1043 1221-1298 NR1H3-1202- 780 868 956 1044 1222-1299 NR1H3-1203- 781 869 957 1045 1223-1300 NR1H3-1204- 782 870 958 1046 1224-1301 NR1H3-1205- 783 871 959 1047 1225-1302 NR1H3-1206- 784 872 960 1048 1226-1303 NR1H3-1208- 785 873 962 1050 1228-1305 NR1H3-1209- 786 874 963 1051 1229-1306 NR1H3-1210- 787 875 964 1052 1230-1307 NR1H3-1211- 788 876 965 1053 1231-1308 NR1H3-1212- 789 877 966 1054 1232-1309 NR1H3-1213- 790 878 967 1055 1233-1310 NR1H3-1214- 791 879 968 1056 1234-1311 NR1H3-1221- 792 880 970 1058 124 1-13 18 NR1H3-1249- 793 881 973 1061 1269-1346 NR1H3-1254- 794 882 975 1063 1274-1351 NR1H3-1255- 795 883 976 1064 1275-1352 NR1H3-1256- 796 884 977 1065 1276-1353 NR1H3-1257- 797 885 978 1066 1277-1354 NR1H3-1260- 798 886 980 1068 1280-1357 NR1H3-1261- 799 887 981 1069 128 1-13 58 NR1H3-1263- 800 888 982 1070 1283-1360 NR1H3-1264- 801 889 983 1071 1284-1361 NR1H3-1405- 802 890 986 1074 1471-1502 NR1H3-1409- 803 891 987 1075 1475-1506 NR1H3-1458- 804 892 993 1081 1524-1555 NR1H3-1464- 805 893 995 1083 1530-1561 NR1H3-1465- 806 894 996 1084 1531-1562 NR1H3-1467- 807 895 997 1085 1533-1564 NR1H3-1469- 808 896 998 1086 1535-1566 NR1H3-1470- 809 897 999 1087 1536-1567 NR1H3-1480- 810 898 1002 1090 1546-1577 NR1H3-1482- 811 899 1004 1092 1548-1579 NR1H3-1524- 812 900 1009 1097 1590-1621 NR1H3-1594- 813 901 1018 1106 1660-1691 NR1H3-1595- 814 902 1019 1107 1661-1692 NR1H3-1596- 815 903 1020 1108 1662 NR1H3-1670- 816 904 1022 1110 1734 NR1H3-1672- 817 905 1024 1112 1736 NR1H3-1673- 818 906 1025 1113 1737 NR1H3-1674- 819 907 1026 1114 1738 NR1H3-1675- 820 908 1027 1115 1739-1766 NR1H3-1676- 821 909 1028 1116 1740-1767 NR1H3-1678- 822 910 1029 1117 1742-1769

The results in FIG. 1B and FIG. 2 demonstrate that GalNAc-conjugated NR1H3 oligonucleotides designed to target human NR1H3 mRNA successfully inhibited human NR1H3 mRNA expression in HDI mice, as determined by a reduction in the amount of human NR1H3 mRNA expression in liver samples from HDI mice treated with GalNAc-conjugated NR1H3 oligonucleotides relative to control HDI mice treated with only PBS. Benchmark controls (NR1H3-769 and NR1H3-1469), which were selected from a prior sequence screening, were used to confirm successful knock-down.

The GalNAc-conjugated NR1H3 oligonucleotides tested in FIG. 1B and FIG. 2 were further validated in repeat assays as shown in FIGS. 3 and 4 using constructs from Table 4 and Table 5. The assays verified knock-down efficiency of each GalNAc-conjugated NR1H3 oligonucleotide, and four constructs were selected for further analysis in non-human primates (NHP).

Example 5: RNAi Oligonucleotide Inhibition of NR1H3 Expression in Non-human Primates In Vivo

Effective GalNAc-NR1H3 constructs identified in the HDI mouse studies were assayed for targeting efficiency in non-human primates. Specifically, GalNAc-conjugated NR1H3 oligonucleotides listed in Table 6 were evaluated in non-naïve cynomolgus monkeys (Macaca fascicularis).

TABLE 6 GalNAc Constructs evaluated in non-human primate Modified Sense Modified strand Antisense strand (SED ID NO) (SED ID NO) NR1H3-1209-1229- 963 1051 1306 NR1H3-1210-1230- 964 1052 1307 NR1H3-1515-1581 1006 1094 NR1H3-1594-1660- 1018 1106 1691

In this study, the monkeys were grouped so that their mean body weights (about 5.4 kg) were comparable between the control and experimental groups. Each cohort contained at least two female and at least two male subjects. The GalNAc-conjugated NR1H3 oligonucleotides were administered subcutaneously at a dose of 1 or 4 mg/kg on Study Day 0, 28, 56, and 112 as outlined in FIG. 5. Blood samples and liver biopsies were collected as outlined in Table 7 and FIG. 5.

TABLE 7 Treatment plan for NHP study Dose (mg/ Dos- DP Blood Liver Group kg) ing GalXC Number Collection Biopsy N A N/A sc PBS N/A −8, 0, 14, −8, 28, 5 28, 56, 112 56, 112 B 1 sc NR1H3-1209- DP18987P: −8, 0, 14, 28, 56, 5 1229-1306 DP18986G 28, 56, 112 112 C 4 sc NR1H3-1209- DP18987P: −8, 0, 14, −8, 28, 5 1229-1306 DP18986G 28, 56, 112 56, 112 D 1 sc NR1H3-1210- DP18989P: −8, 0, 14, 28, 56, 5 1230-1307 DP18988G 28, 56, 112 112 E 4 sc NR1H3-1210- DP18989P: −8, 0, 14, −8, 28, 5 1230-1307 DP18988G 28, 56, 112 56, 112 F 1 sc NR1H3-1515- DP20645P: −8, 0, 14, 28, 56, 5 1581 DP20644G 28, 56, 112 112 G 4 sc NR1H3-1515- DP20645P: −8, 0, 14, −8, 28, 5 1581 DP20644G 28, 56, 112 56, 112 H 1 sc NR1H3-1594- DP19040P: −8, 0, 14, 28, 56, 4 1660-1691 DP19039G 28, 56, 112 112 I 4 sc NR1H3-1594- DP19040P: −8, 0, 14, −8, 28, 5 1660-1691 DP19039G 28, 56, 112 56, 112

At each time point, total RNA derived from the liver biopsy samples was subjected to qRT-PCR analysis to measure NR1H3 mRNA in oligonucleotide-treated monkeys relative to those treated with a comparable volume of PBS. To normalize the data, the measurements were made relative to the reference gene, PPIB (Rh02802984_m1 (Taqman)). The following SYBR assays purchased from Integrated DNA Technologies were used to evaluate gene expressions: Forward-942: GTCTCTGTGCAGGAGATAGTTG (SEQ ID NO: 1517), Reverse-1399: GGAGGCTCACCAGTTTCATTA (SEQ ID NO: 1518). As shown in Table 8 (Day 28), treating NHPs with the GalNAc-conjugated NR1H3 oligonucleotides listed in Table 6 inhibited NR1H3 expression in the liver, as determined by a reduced amount of NR1H3 mRNA in liver samples from oligonucleotide-treated NHPs relative to NHPs treated with PBS. Days 56 and 112 were also measured (Table 8). These results demonstrate that treating NHPs with the GalNAc-conjugated NR1H3 oligonucleotides reduces the amount of NR1H3 mRNA in the liver in a dose dependent manner.

TABLE 8 NR1H3 mRNA remaining after treatment with the indicated NR1H3-GalNAc in the liver from the oligonucleotide-treated NHP NR1H3 Gene Expression (% Time-Matched PBS) −1209 −1210 −1515 −1594 1 4 1 4 1 4 1 4 mg/ mg/ mg/ mg/ mg/ mg/ mg/ mg/ PBS kg kg kg kg kg kg kg kg Day 28 Animal 1 107.3 58.6 35.6 60.1 45.1 95.8 55.4 111.6 80.4 Animal 2 116.6 62.4 27.8 48.5 34.7 101.3 NS 108.3 103.6 Animal 3 122.1 79.4 44.5 73.8 35.7 111.8 74.1 145.5 45.9 Animal 4 77.4 78.5 50.5 65.1 27.5 70.0 45.1 195.4 73.2 Animal 5 76.6 89.2 37.4 77.5 45.2 78.9 34.9 NS 68.5 Average 100.0 73.6 39.2 65.0 37.6 91.6 52.4 140.2 74.3 SEM 9.7 5.7 3.9 5.1 3.4 7.6 8.4 20.2 9.3 Day 56 Animal 1 96.7 72.9 29.0 43.7 39.0 59.7 30.0 67.7 78.2 Animal 2 115.0 60.1 29.7 75.9 32.1 68.7 NS 85.1 103.4 Animal 3 87.1 52.7 32.6 36.8 40.4 48.1 45.0 104.3 70.0 Animal 4 103.4 34.9 45.0 51.9 26.9 43.6 37.3 76.2 72.1 Animal 5 97.8 45.9 32.3 55.9 36.0 47.1 31.1 NS 72.4 Average 100.0 53.3 33.7 52.8 34.9 53.4 35.9 83.3 79.2 SEM 4.6 6.4 2.9 6.6 2.5 4.7 3.4 7.8 6.2 Day 112 Animal 1 113.2 44.2 27.3 34.4 33.1 52.8 46.8 56.6 34.8 Animal 2 106.6 56.2 21.7 42.8 33.0 36.2 NS 57.9 31.2 Animal 3 100.2 59.6 22.1 33.4 29.6 46.2 45.7 48.5 44.2 Animal 4 103.1 47.8 45.0 44.9 33.1 44.1 44.9 65.7 32.1 Animal 5 77.0 55.9 34.4 45.3 32.1 52.6 37.6 NS 33.6 Average 100.0 52.7 30.1 40.2 32.2 46.4 43.8 57.2 35.2 SEM 6.2 2.9 4.4 2.6 0.7 3.1 2.1 3.5 2.3 NS = no sample

To confirm if the GalNAc conjugated NR1H3 were specific targeting NR1H3, both NR1H3 and NR1H2 expression was evaluated in liver samples. Non-human primates treated with 4 mg/kg of GalNAc-conjugated NR1H3 were assayed for expression at days 0, 28, 56, and 112 in the liver for knock-down (KD) of NR1H3 mRNA in (Table 9), and NR1H2 (Table 10). The results demonstrate that the constructs are specific to NR1H3 and do not have significant off target effects for NR1H2.

TABLE 9 NR1H3 mRNA remaining after treatment with the indicated NR1H3-GalNAc in NHP NR1H3 Gene Expression (% Time Matched PBS) 4 mg/kg PBS −1209 −1210 −1515 −1594 Day −6 Animal 1 65.8 136.6 204.3 103.8 NS Animal 2 102.4 78.1 113.3 49.3 80.3 Animal 3 86.1 101.0 150.2 94.0 104.3 Animal 4 137.3 89.9 155.0 82.8 109.7 Animal 5 108.4 90.8 92.5 83.1 124.2 Average 100.0 99.3 143.1 82.6 104.6 SEM 11.9 10.0 19.2 9.2 9.1 Day 28 Animal 1 107.3 35.6 45.1 55.4 80.4 Animal 2 116.6 27.8 34.7 NS 103.6 Animal 3 122.1 44.5 35.7 74.1 45.9 Animal 4 77.4 50.5 27.5 45.1 73.2 Animal 5 76.6 37.4 45.2 34.9 68.5 Average 100.0 39.2 37.6 52.4 74.3 SEM 9.7 3.9 3.4 8.4 9.3 Day 56 Animal 1 96.7 29.0 39.0 30.0 78.2 Animal 2 115.0 29.7 32.1 NS 103.4 Animal 3 87.1 32.6 40.4 45.0 70.0 Animal 4 103.4 45.0 26.9 37.3 72.1 Animal 5 97.8 32.3 36.0 31.1 72.4 Average 100.0 33.7 34.9 35.9 79.2 SEM 4.6 2.9 2.5 3.4 6.2 Day 112 Animal 1 113.2 27.3 33.1 46.8 34.8 Animal 2 106.6 21.7 33.0 NS 31.2 Animal 3 100.2 22.1 29.6 45.7 44.2 Animal 4 103.1 45.0 33.1 44.9 32.1 Animal 5 77.0 34.4 32.1 37.6 33.6 Average 100.0 30.1 32.2 43.8 35.2 SEM 6.2 4.4 0.7 2.1 2.3 NS = no sample

TABLE 10 NR1H2 mRNA remaining after treatment with the indicated NR1H3-GalNAc in NHP NR1H2 Gene Expression (% Time Matched PBS) 4 mg/kg PBS −1209 −1210 −1515 −1594 Day −6 Animal 1 119.7 84 324.9 79.8 NS Animal 2 96.3 107.5 116.1 89.3 175.9 Animal 3 105.7 86.2 106.6 103 151.1 Animal 4 82.1 105.7 672 127.9 113.2 Animal 5 96.3 134.9 126.7 101.6 113.9 Average 100.0 103.7 269.3 100.3 138.5 SEM 6.2 9.2 108.5 8.1 15.3 Day 28 Animal 1 101 80.2 122.2 102.7 117.5 Animal 2 123.3 80.9 103.7 NS 130 Animal 3 111.8 78.1 107.3 87.8 61.2 Animal 4 88.5 120.4 113.7 98.3 80.2 Animal 5 75.3 129.4 102.7 97.1 75.4 Average 100.0 97.8 109.9 96.5 92.9 SEM 8.4 11.2 3.6 3.1 13.1 Day 56 Animal 1 118.5 127.9 119.2 90.9 88.5 Animal 2 118.4 98.6 99.6 NS 112 Animal 3 90.9 91 131.8 76.3 103 Animal 4 88.5 115.4 117.8 100.7 121.1 Animal 5 83.8 107.6 87.1 85.5 119.4 Average 100.0 108.1 111.1 88.4 108.8 SEM 7.6 6.4 7.9 5.1 6.0 Day 112 Animal 1 105.6 114.2 107.9 95.6 89.6 Animal 2 108.5 81.5 106.8 NS 80.8 Animal 3 119.1 76.7 118.4 90.5 96.8 Animal 4 100.4 121.1 97.2 95.4 98.6 Animal 5 66.4 99.1 104.8 111.9 98.1 Average 100.0 98.5 107.0 98.4 92.8 SEM 8.9 8.7 3.4 4.7 3.4

Taken together, these results show that GalNAc-conjugated NR1H3 oligonucleotides designed to target human NR1H3 mRNA inhibit total NR1H3 expression in vivo (as determined by the reduction of the amount of NR1H3 mRNA).

Example 6

In order to determine the effect of hepatic NR1H3 knockdown on liver and plasma triglycerides and total plasma cholesterol, C57B1 mice fed a high fat, high fructose, high cholesterol (HFFC-NASH) diet were administrated a NR1H3 GalNac siRNA probe specifically designed to reduce NR1H3 expression in mice. The compound was administrated by subcutaneous injection 3 mg/kg once a week for 4 weeks. The respective vehicle treated groups (chow and HFFC-NASH diet) were treated with PBS.

As seen in Table 11, hepatocyte specific knockdown (KD) of murine NR1H3-specific GalNac siRNA led to a significant decrease in murine NR1H3 transcript expression in the liver of treated animals as compared to vehicle. Treatment leading to such hepatic NR1H3 mRNA reduction in turn induced reductions in liver triglycerides, plasma triglyceride and plasma total cholesterol. Furthermore, genes involved in hepatic de novo lipogenesis (fatty acid synthase (Fasn) and Acetyl-CoA carboxylase 2 (Acc2)) were decreased by treatment with the murine NR1H3-specific GalNac siRNA. In conclusion, hepatocyte-specific knockdown of NR1H3 mRNA in a mouse model for NAFLD led to significant improvement in NASH related dyslipidemia.

TABLE 11 NASH p-value diet/NR1H3 NASH/ CHOW diet NASH KD NASH AVG ± ST. AVG ± ST. AVG ± ST. NR1H3 DEV. DEV. DEV. KD Liver 9.39 ± 2.88 47.00 ± 12.56 19.39 ± 11.07 <0.0001 triglycerides mg/g liver Plasma 1.31 ± 0.31 0.86 ± 0.21 0.46 ± 0.11 0.0036 triglycerides mM Plasma total 2.06 ± 0.21 4.19 ± 0.54 3.37 ± 0.67 0.0145 cholesterol mM NR1H3  100 ± 5.27 106.19 ± 8.75  43.88 ± 6.27  <0.0001 mRNA expression Fasn mRNA   100 ± 44.53 56.60 ± 27.23 17.58 ± 6.06  0.0327 expression Acc2 mRNA   100 ± 20.30 43.34 ± 21.89 12.21 ± 4.31  0.0034 expression

Example 7: GalNAc-Conjugated siRNA Targeting NR1H3 for Knock Down in Obese Rhesus Monkeys Fed a High Cholesterol Diet

A GalNAc-conjugated NR1H3 oligonucleotide (sense strand SEQ ID NO: 964 antisense strand SEQ ID NO: 1052) was administered to obese rhesus monkeys fed a high cholesterol diet (0.06% cholesterol). Eight obese rhesus monkeys fed a high cholesterol diet (0.06% cholesterol) for more than 4 years, and with a body weight ranging from 8-25 kg, were dosed with 4 mg/kg lead at weeks 0, 4 and 8 and study was terminated at week 12. A liver biopsy (week −3) and an ultrasound scan of the liver (week −1) were performed prior to dosing of the animals. Liver enzymes and plasma lipids were determined prior to dosing and every 2 weeks posttreatment to assess potential adverse effects. At the end of the study, liver and plasma samples were collected to measure the effect of NR1H3a knock down on lipid and cholesterol metabolism, hepatic genes involved in these pathways, as well as liver histology.

At the end of the study NR1H3a mRNA in the liver was decreased 50%. mRNA is calculated as A/A Ct levels relative to 18s gene expression in each sample. As NR1H3a is expressed in other liver cells, e.g. the Kupffer cells, a full knockdown of NR1H3a was not expected from a liver homogenate.

The plasma levels of liver enzymes and plasma levels of lipids are presented in Table 12. During the treatment period, there was no change in the plasma level of alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT) or total bilirubin (TB), while a small increase was observed in aspartate aminotransferase (AST) after 8 and 10 weeks of treatment. During the treatment period, there was no change in the plasma level total cholesterol (TC) or low-density lipoprotein cholesterol (LDL C), while a significant increase in high-density lipoprotein cholesterol (HDL C) was observed already after 2 weeks of treatment. After 12 weeks of treatment a significant decrease in plasma triglycerides (TG) was observed. In Table 12, data represent mean±standard error of the mean. Baseline is the average of measures from week −4 to week 0 (pre-dose). Statistics are done relative to baseline: One-Way ANOVA. P*<0.05 P**<0.01, P***<0.001.

TABLE 12 Liver enzymes and plasma lipids in response to NR1H3a KD in obese rhesus monkeys. Plasma Plasma Total AST ALT GGT TBili TG Cholesterol HDL-C LDL-C (IU/L) (IU/L) (IU/L) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) Baseline 31.9 ± 1.5   55.6 ± 7.1 55.1 ± 4.2 0.21 ± 0.01   110 ± 19   206 ± 21.9 80 ± 4.6  107 ± 17.3 Week 2 32.9 ± 2.9   58.4 ± 6.2 55.6 ± 5.2 0.17 ± 0.03  84.9 ± 10.3  209 ± 20   98 ± 6.0**  98 ± 14.5 Week 4 36.6 ± 4.1   68.9 ± 9.3 58.0 ± 3.8 0.18 ± 0.02   103 ± 20.2  210 ± 15   107 ± 4.3*** 101 ± 10.8 Week 6 38.5 ± 3.2   66.3 ± 6.0 49.9 ± 3.2 0.23 ± 0.02  74.1 ± 6.7  208 ± 16   102 ± 6.4**  98 ± 9.8 Week 8 42.5 ± 2.5*** 70.4 ± 9.0 54.1 ± 4.5 0.15 ± 0.02* 93.3 ± 18.0  211 ± 14   105 ± 6.2**  104 ± 9.4  Week 10 39.5 ± 2.8**  58.5 ± 3.7 60.0 ± 3.3 0.17 ± 0.02  91.6 ± 12.4  219 ± 15   107 ± 4.9**  105 ± 10.4 Week 12 36.1 ± 2.1   59.3 ± 7.0 62.8 ± 3.5 0.16 ± 0.02* 84.9 ± 17.2* 214 ± 14   108 ± 4.3**  116 ± 11.1

The effect of NR1H3a knock down on liver triglycerides and liver cholesterol is presented in Table 13. No significant change in liver triglycerides or cholesterol was observed. However, a tendency (p=0.055, paired t-test) towards a decrease in liver stiffness as measured by FibroScan™ was observed in response to hepatic NR1H3a knock down. In Table 13 data represent mean±standard error of the mean analyzed by a paired t-test. One monkey was excluded from the FibroScan™ analysis as it was not fully sedated during the second scan.

TABLE 13 TG and cholesterol levels and FibroScan ™ liver stiffness in obese rhesus monkeys Baseline Week 13-14 Liver triglycerides (mg/dL) 40.9 ± 6.6 40.0 ± 5.5 Liver cholesterol (mg/dL) 42.6 ± 3.9 41.4 ± 3.0 Liver stiffness kPa  5.7 ± 0.5  4.3 ± 0.2

From the study, it can be concluded that knockdown of NR1H3a in hepatocytes does not cause hepatic cholesterol accumulation in obese monkeys fed a high cholesterol diet. An increased in plasma HDL C was observed 2 weeks after dosing, while a lowering of plasma TG was observed at week 12. No effect on liver TG was observed but none of the monkeys had steatosis at the start of the study. However, a tendency toward a decrease in liver stiffness was observed in response to hepatic NR1H3a knockdown.

List of Embodiments

Embodiment 1. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 2. The RNAi oligonucleotide of embodiment 1, wherein the sense strand is 15 to 50 nucleotides in length.

Embodiment 3. The RNAi oligonucleotide of embodiments 1 or 2, wherein the sense strand is 18 to 36 nucleotides in length.

Embodiment 4. The RNAi oligonucleotide of any one of embodiments 1 to 3, wherein the antisense strand is 15 to 30 nucleotides in length.

Embodiment 5. The RNAi oligonucleotide of any one of embodiments 1 to 4, wherein the antisense strand is 22 nucleotides in length and wherein antisense strand and the sense strand form a duplex region of at least 19 nucleotides in length, optionally at least 20 nucleotides in length.

Embodiment 6. The RNAi oligonucleotide of any one of embodiments 1 to 5, wherein the region of complementarity is at least 19 contiguous nucleotides in length, optionally at least 20 nucleotides in length.

Embodiment 7. The RNAi oligonucleotide of any one of embodiments 1 to 6, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length.

Embodiment 8. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 15 to 50 nucleotides in length and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 9. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 15 to 50 nucleotides in length and an antisense strand of 15 to 30 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 10. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 15 to 50 nucleotides in length and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 11. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 18 to 36 nucleotides in length and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 12. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 18 to 36 nucleotides in length and an antisense strand of 22 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 13. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 18 to 36 nucleotides in length and an antisense strand of 22 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 14. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 36 nucleotides in length and an antisense strand of 22 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 15. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand of 36 nucleotides in length and an antisense strand of 22 nucleotides in length, wherein the sense strand and the antisense strand form a duplex region of at least 19 nucleotides in length, optionally 20 nucleotides in length, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, wherein S1 is complementary to S2, and wherein L forms a loop between S1 and S2 of 3-5 nucleotides in length, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is 19 contiguous nucleotides in length, optionally 20 nucleotides in length.

Embodiment 16. The RNAi oligonucleotide of any one of embodiments 7 and 13-15, wherein L is a triloop or a tetraloop.

Embodiment 17. The RNAi oligonucleotide of embodiment 16, wherein L is a tetraloop.

Embodiment 18. The RNAi oligonucleotide of embodiment 17, wherein the tetraloop comprises the sequence 5′-GAAA-3′.

Embodiment 19. The RNAi oligonucleotide of any one of embodiments 16-18, wherein the S1 and S2 are 1-10 nucleotides in length and have the same length.

Embodiment 20. The RNAi oligonucleotide of embodiment 19, wherein S1 and S2 are 1 nucleotide, 2 nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides, 7 nucleotides, 8 nucleotides, 9 nucleotides, or 10 nucleotides in length.

Embodiment 21. The RNAi oligonucleotide of embodiment 20, wherein S1 and S2 are 6 nucleotides in length.

Embodiment 22. The RNAi oligonucleotide of any one of embodiments 16 to 21, wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121).

Embodiment 23. The RNAi oligonucleotide of any one of embodiments 1 to 22, wherein the antisense strand comprises a 3′-overhang sequence of one or more nucleotides in length.

Embodiment 24. The RNAi oligonucleotide of embodiment 23, wherein the 3′-overhang sequence is 2 nucleotides in length, optionally wherein the 3′-overhang sequence is GG.

Embodiment 25. The RNAi oligonucleotide of any one of the preceding embodiments, wherein the oligonucleotide comprises at least one modified nucleotide.

Embodiment 26. The RNAi oligonucleotide of embodiment 25, wherein the modified nucleotide comprises a 2′-modification.

Embodiment 27. The RNAi oligonucleotide of embodiment 26, wherein the 2′-modification is a modification selected from 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid.

Embodiment 28. The RNAi oligonucleotide of any one of embodiments 25 to 27, wherein all nucleotides comprising the oligonucleotide are modified, optionally wherein the modification is a 2′-modification selected from 2′-fluoro and 2′-O-methyl.

Embodiment 29. The RNAi oligonucleotide of any one of embodiments 25-28, wherein about 10-15%, 10%, 11%, 12%, 13%, 14%, or 15% of the nucleotides of the sense strand comprise a 2′-fluoro modification.

Embodiment 30. The RNAi oligonucleotide of any one of embodiments 25-29, wherein about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the antisense strand comprise a 2′-fluoro modification.

Embodiment 31. The RNAi oligonucleotide of any one of embodiments 25-30, wherein about 25-35%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of the oligonucleotide comprise a 2′-fluoro modification

Embodiment 32. The RNAi oligonucleotide of any one of embodiments 25-31, wherein the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein positions 8-11 comprise a 2′-fluoro modification.

Embodiment 33. The RNAi oligonucleotide of any one of embodiments 25-32, wherein the antisense strand comprises 22 nucleotides with positions 1-22 from 5′ to 3′, and wherein positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2′-fluoro modification.

Embodiment 34. The RNAi oligonucleotide of any one of embodiments 25-33, wherein the remaining nucleotides comprise a 2′-O-methyl modification.

Embodiment 35. The RNAi oligonucleotide of any one of the preceding embodiments, wherein the oligonucleotide comprises at least one modified internucleotide linkage.

Embodiment 36. The RNAi oligonucleotide of embodiment 35, wherein the at least one modified internucleotide linkage is a phosphorothioate linkage.

Embodiment 37. The RNAi oligonucleotide of any one of the preceding embodiments, wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog.

Embodiment 38. The RNAi oligonucleotide of embodiment 37, wherein the phosphate analog is oxymethylphosphonate, vinylphosphonate or malonylphosphonate, optionally wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy.

Embodiment 39. The RNAi oligonucleotide of any one of the preceding embodiments, wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands.

Embodiment 40. The RNAi oligonucleotide of embodiment 39, wherein each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide or lipid.

Embodiment 41. The RNAi oligonucleotide of embodiment 39, wherein each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety.

Embodiment 42. The RNAi oligonucleotide of embodiment 35, wherein the GalNAc moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety.

Embodiment 43. The RNAi oligonucleotide of any one of embodiments 16 to 38, wherein up to 4 nucleotides of L of the stem-loop are each conjugated to a monovalent GalNAc moiety.

Embodiment 44. The RNAi oligonucleotide of any one of embodiments 1 to 43, wherein the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 769-856 or 1519-1552.

Embodiment 45. The RNAi oligonucleotide of any one of embodiments 1 to 44, wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 857-944.

Embodiment 46. The RNAi oligonucleotide of any one of embodiments 1 to 45, wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively.

Embodiment 47. The RNAi oligonucleotide of any one of embodiments 1 to 46, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 786, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 874.

Embodiment 48. The RNAi oligonucleotide of any one of embodiments 1 to 46, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 787, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 875.

Embodiment 49. The RNAi oligonucleotide of any one of embodiments 1 to 46, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1537, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 929.

Embodiment 50. The RNAi oligonucleotide of any one of embodiments 1 to 46, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 813, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 901.

Embodiment 51. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein all nucleotides comprising the sense strand and antisense strand are modified, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 52. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein all nucleotides comprising the sense strand and antisense strand are modified, wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 53. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein all nucleotides comprising the sense strand and antisense strand are modified, wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 54. An RNAi oligonucleotide for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein all nucleotides comprising the sense strand and the antisense strand are modified, wherein the antisense strand and the sense strand comprise one or more 2′-fluoro and 2′-O-methyl modified nucleotides and at least one phosphorothioate linkage, wherein the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 55. The RNAi oligonucleotide of any one of embodiments 1-54, wherein the sense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 945-1032.

Embodiment 56. The RNAi oligonucleotide of any one of embodiments 1-55, wherein the antisense strand comprises a nucleotide sequence of any one of SEQ ID NOs: 1033-1120.

Embodiment 57. The RNAi oligonucleotide of any one of embodiments 1-56, wherein the sense and antisense strands comprise nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 945 and 1033, respectively; (b) SEQ ID NOs: 946 and 1034, respectively; (c) SEQ ID NOs: 947 and 1035, respectively; (d) SEQ ID NOs: 948 and 1036, respectively; (e) SEQ ID NOs: 949 and 1037, respectively; (f) SEQ ID NOs: 950 and 1038, respectively; (g) SEQ ID NOs: 951 and 1039, respectively; (h) SEQ ID NOs: 952 and 1040, respectively; (i) SEQ ID NOs: 953 and 1041, respectively; (j) SEQ ID NOs: 954 and 1042, respectively; (k) SEQ ID NOs: 955 and 1043, respectively; (l) SEQ ID NOs: 956 and 1044 respectively; (m) SEQ ID NOs: 957 and 1045, respectively; (n) SEQ ID NOs: 958 and 1046, respectively; (o) SEQ ID NOs: 959 and 1047, respectively; (p) SEQ ID NOs: 960 and 1048, respectively; (q) SEQ ID NOs: 961 and 1049, respectively; (r) SEQ ID NOs: 962 and 1050, respectively; (s) SEQ ID NOs: 963 and 1051, respectively; (t) SEQ ID NOs: 964 and 1052, respectively; (u) SEQ ID NOs: 965 and 1053, respectively; (v) SEQ ID NOs: 966 and 1054, respectively; (w) SEQ ID NOs: 967 and 1055, respectively; (x) SEQ ID NOs: 968 and 1056, respectively; (y) SEQ ID NOs: 969 and 1057, respectively; (z) SEQ ID NOs: 970 and 1058, respectively; (aa) SEQ ID NOs: 971 and 1059, respectively; (bb) SEQ ID NOs: 972 and 1060, respectively; (cc) SEQ ID NOs: 973 and 1061, respectively; (dd) SEQ ID NOs: 974 and 1062, respectively; (ee) SEQ ID NOs: 975 and 1063, respectively; (ff) SEQ ID NOs: 976 and 1064, respectively; (gg) SEQ ID NOs: 977 and 1065, respectively; (hh) SEQ ID NOs: 978 and 1066, respectively; (ii) SEQ ID NOs: 979 and 1067, respectively; (jj) SEQ ID NOs: 980 and 1068, respectively; (kk) SEQ ID NOs: 981 and 1069, respectively; (ll) SEQ ID NOs: 982 and 1070, respectively; (mm) SEQ ID NOs: 983 and 1071, respectively; (nn) SEQ ID NOs: 984 and 1072, respectively; (oo) SEQ ID NOs: 985 and 1073, respectively; (pp) SEQ ID NOs: 986 and 1074, respectively; (qq) SEQ ID NOs: 987 and 1075, respectively; (rr) SEQ ID NOs: 988 and 1076, respectively; (ss) SEQ ID NOs: 989 and 1077, respectively; (tt) SEQ ID NOs: 990 and 1078, respectively; (uu) SEQ ID NOs: 991 and 1079, respectively; (vv) SEQ ID NOs: 992 and 1080, respectively; (ww) SEQ ID NOs: 993 and 1081, respectively; (xx) SEQ ID NOs: 994 and 1082, respectively; (yy) SEQ ID NOs: 995 and 1083, respectively; (zz) SEQ ID NOs: 996 and 1084, respectively; (aaa) SEQ ID NOs: 997 and 1085, respectively; (bbb) SEQ ID NOs: 998 and 1086, respectively; (ccc) SEQ ID NOs: 999 and 1087, respectively; (ddd) SEQ ID NOs: 1000 and 1088, respectively; (eee) SEQ ID NOs: 1001 and 1089, respectively; (fff) SEQ ID NOs: 1002 and 1090, respectively; (ggg) SEQ ID NOs: 1003 and 1091, respectively; (hhh) SEQ ID NOs: 1004 and 1092 respectively; (iii) SEQ ID NOs: 1005 and 1093 respectively; (jjj) SEQ ID NOs: 1006 and 1094, respectively; (kkk) SEQ ID NOs: 1007 and 1095, respectively; (lll) SEQ ID NOs: 1008 and 1096, respectively; (mmm) SEQ ID NOs: 1009 and 1097, respectively; (nnn) SEQ ID NOs: 1010 and 1098, respectively; (ooo) SEQ ID NOs: 1011 and 1099, respectively; (ppp) SEQ ID NOs: 1012 and 1100, respectively; (qqq) SEQ ID NOs: 1013 and 1101, respectively; (rrr) SEQ ID NOs: 1014 and 1102 respectively; (sss) SEQ ID NOs: 1015 and 1103, respectively; (ttt) SEQ ID NOs: 1016 and 1104, respectively; (uuu) SEQ ID NOs: 1017 and 1105, respectively; (vvv) SEQ ID NOs: 1018 and 1106, respectively; (www) SEQ ID NOs: 1019 and 1107, respectively; (xxx) SEQ ID NOs: 1020 and 1108, respectively; (yyy) SEQ ID NOs: 1021 and 1109, respectively; (zzz) SEQ ID NOs: 1022 and 1110, respectively; (aaaa) SEQ ID NOs: 1023 and 1111, respectively; (bbbb) SEQ ID NOs: 1024 and 1112, respectively; (cccc) SEQ ID NOs: 1025 and 1113, respectively; (dddd) SEQ ID NOs: 1026 and 1114, respectively; (eeee) SEQ ID NOs: 1027 and 1115, respectively; (ffff) SEQ ID NOs: 1028 and 1116, respectively; (gggg) SEQ ID NOs: 1029 and 1117, respectively; (hhhh) SEQ ID NOs: 1030 and 1118, respectively; (iiii) SEQ ID NOs: 1031 and 1119, respectively; and, (jjjj) SEQ ID NOs: 1032 and 1120, respectively.

Embodiment 58. The RNAi oligonucleotide of any one of embodiments 1-57, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 963 and 1051, respectively.

Embodiment 59. The RNAi oligonucleotide of any one of embodiments 1-57, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 964 and 1052, respectively.

Embodiment 60. The RNAi oligonucleotide of any one of embodiments 1-57, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1006 and 1094, respectively.

Embodiment 61. The RNAi oligonucleotide of any one of embodiments 1-57, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1018 and 1106, respectively.

Embodiment 62. An RNAi oligonucleotide for inhibiting expression of NR1H3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a NR1H3 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of 5′-mCs-mU-mC-mA-mA-mG-mG-fA-fU-fU-fU-mC-mA-mG-mU-mU-mA-mU-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 963), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-40-mUs]-fUs-fAs-fU-fA-mA-fC-mU-mG-fA-mA-mA-mU-fC-mC-mU-mU-mG-mA-mGs-mGs-mG-3′ (SEQ ID NO: 1051), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

Embodiment 63. An RNAi oligonucleotide for inhibiting expression of NR1H3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a NR1H3 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of 5′-mUs-mC-mA-mA-mG-mG-mA-fU-fU-fU-fC-mA-mG-mU-mU-mA-mU-mA-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 964) and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-40-mUs]-fUs-fUs-fA-fU-mA-fA-mC-mU-fG-mA-mA-mA-fU-mC-mC-mU-mU-mG-mAs-mGs-mG-3′ (SEQ ID NO: 1052), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

Embodiment 64. An RNAi oligonucleotide for inhibiting expression of NR1H3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a NR1H3 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of 5′-mAs-mG-mC-mA-mG-mC-mG-fU-fC-fC-fA-mC-mU-mC-mA-mG-mA-mG-mC-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1006), and wherein the antisense strand comprises the sequence and all of the modifications of 5′[MePhosphonate-40-mUs]-fGs-fCs-fU-fC-mU-fG-mA-mG-fU-mG-mG-mA-fC-mG-mC-mU-mG-mC-mUs-mGs-mG-3′ (SEQ ID NO: 1094), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

Embodiment 65. A double stranded RNAi oligonucleotide (dsRNAi) for inhibiting expression of NR1H3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a NR1H3 RNA transcript, wherein the sense strand comprises the sequence and all of the modifications of 5′-mAs-mU-mG-mU-mG-mC-mA-fC-fG-fA-fA-mU-mG-mA-mC-mU-mG-mU-mU-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1018), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fAs-fAs-fC-fA-mG-fU-mC-mA-fU-mU-mC-mG-fU-mG-mC-mA-mC-mA-mUs-mGs-mG-3′ (SEQ ID NO: 1106), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

Embodiment 66. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of the RNAi oligonucleotide of any one of the preceding embodiments, or pharmaceutical composition thereof, thereby treating the subject.

Embodiment 67. A pharmaceutical composition comprising the RNAi oligonucleotide of any one of embodiments 1 to 65, and a pharmaceutically acceptable carrier, delivery agent or excipient.

Embodiment 68. A method of delivering an oligonucleotide to a subject, the method comprising administering pharmaceutical composition of embodiment 67 to the subject.

Embodiment 69. A method for reducing NR1H3 expression in a cell, a population of cells or a subject, the method comprising the step of:

-   -   i. contacting the cell or the population of cells with the RNAi         oligonucleotide of any one of embodiments 1 to 65, or the         pharmaceutical composition of embodiment 67; or     -   ii. administering to the subject the RNAi oligonucleotide of any         one of embodiments 1 to 65, or the pharmaceutical composition of         embodiment 67.

Embodiment 70. The method of embodiment 69, wherein reducing NR1H3 expression comprises reducing an amount or level of NR1H3 mRNA, an amount or level of NR1H3 protein, or both.

Embodiment 71. The method of embodiment 69 or 70, wherein the subject has a disease, disorder or condition associated with NR1H3 expression.

Embodiment 72. The method of embodiment 66 or 71, wherein the disease, disorder or condition associated with NR1H3 expression is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 73. The method of any one of embodiments 66 and 69 to 72, wherein the RNAi oligonucleotide, or pharmaceutical composition, is administered in combination with a second composition or therapeutic agent.

Embodiment 74. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein the antisense strand comprises a region of complementarity to a NR1H3 mRNA target sequence of any one of SEQ ID NOs: 1-384, and wherein the region of complementarity is at least 15 contiguous nucleotides in length.

Embodiment 75. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi oligonucleotide comprising a sense strand and an antisense strand selected from a row set forth in Table 4 or Table 5, or pharmaceutical composition thereof, thereby treating the subject.

Embodiment 76. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 769 and 857, respectively; (b) SEQ ID NOs: 770 and 858, respectively; (c) SEQ ID NOs: 771 and 859, respectively; (d) SEQ ID NOs: 772 and 860, respectively; (e) SEQ ID NOs: 773 and 861, respectively; (f) SEQ ID NOs: 774 and 862, respectively; (g) SEQ ID NOs: 775 and 863, respectively; (h) SEQ ID NOs: 776 and 864, respectively; (i) SEQ ID NOs: 777 and 865, respectively; (j) SEQ ID NOs: 778 and 866, respectively; (k) SEQ ID NOs: 779 and 867, respectively; (l) SEQ ID NOs: 780 and 868, respectively; (m) SEQ ID NOs: 781 and 869, respectively; (n) SEQ ID NOs: 782 and 870, respectively; (o) SEQ ID NOs: 783 and 871, respectively; (p) SEQ ID NOs: 784 and 872, respectively; (q) SEQ ID NOs: 785 and 873, respectively; (r) SEQ ID NOs: 786 and 874, respectively; (s) SEQ ID NOs: 787 and 875, respectively; (t) SEQ ID NOs: 788 and 876, respectively; (u) SEQ ID NOs: 789 and 877, respectively; (v) SEQ ID NOs: 790 and 878, respectively; (w) SEQ ID NOs: 791 and 879, respectively; (x) SEQ ID NOs: 792 and 880, respectively; (y) SEQ ID NOs: 793 and 881, respectively; (z) SEQ ID NOs: 794 and 882, respectively; (aa) SEQ ID NOs: 795 and 883, respectively; (bb) SEQ ID NOs: 796 and 884, respectively; (cc) SEQ ID NOs: 797 and 885, respectively; (dd) SEQ ID NOs: 798 and 886, respectively; (ee) SEQ ID NOs: 799 and 887, respectively; (ff) SEQ ID NOs: 800 and 888, respectively; (gg) SEQ ID NOs: 801 and 889, respectively; (hh) SEQ ID NOs: 802 and 890, respectively; (ii) SEQ ID NOs: 803 and 891, respectively; (jj) SEQ ID NOs: 804 and 892, respectively; (kk) SEQ ID NOs: 805 and 893, respectively; (ll) SEQ ID NOs: 806 and 894, respectively; (mm) SEQ ID NOs: 807 and 895, respectively; (nn) SEQ ID NOs: 808 and 896, respectively; (oo) SEQ ID NOs: 809 and 897, respectively; (pp) SEQ ID NOs: 810 and 898, respectively; (qq) SEQ ID NOs: 811 and 899, respectively; (rr) SEQ ID NOs: 812 and 900, respectively; (ss) SEQ ID NOs: 813 and 901, respectively; (tt) SEQ ID NOs: 814 and 902, respectively; (uu) SEQ ID NOs: 815 and 903, respectively; (vv) SEQ ID NOs: 816 and 904, respectively; (ww) SEQ ID NOs: 817 and 905, respectively; (xx) SEQ ID NOs: 818 and 906, respectively; (yy) SEQ ID NOs: 819 and 907, respectively; (zz) SEQ ID NOs: 820 and 908, respectively; (aaa) SEQ ID NOs: 821 and 909, respectively; (bbb) SEQ ID NOs: 822 and 910, respectively; (ccc) SEQ ID NOs: 823 and 911, respectively; (ddd) SEQ ID NOs: 824 and 912, respectively; (eee) SEQ ID NOs: 825 and 913, respectively; (fff) SEQ ID NOs: 826 and 914, respectively; (ggg) SEQ ID NOs: 827 and 915, respectively; (hhh) SEQ ID NOs: 828 and 916, respectively; (iii) SEQ ID NOs: 829 and 917, respectively; (jjj) SEQ ID NOs: 830 and 918, respectively; (kkk) SEQ ID NOs: 831 and 919, respectively; (lll) SEQ ID NOs: 832 and 920, respectively; (mmm) SEQ ID NOs: 833 and 921, respectively; (nnn) SEQ ID NOs: 834 and 922, respectively; (ooo) SEQ ID NOs: 835 and 923, respectively; (ppp) SEQ ID NOs: 836 and 924, respectively; (qqq) SEQ ID NOs: 837 and 925, respectively; (rrr) SEQ ID NOs: 838 and 926, respectively; (sss) SEQ ID NOs: 839 and 927, respectively; (ttt) SEQ ID NOs: 840 and 928, respectively; (uuu) SEQ ID NOs: 1537 and 929, respectively; (vvv) SEQ ID NOs: 842 and 930, respectively; (www) SEQ ID NOs: 843 and 931, respectively; (xxx) SEQ ID NOs: 844 and 932, respectively; (yyy) SEQ ID NOs: 845 and 933, respectively; (zzz) SEQ ID NOs: 846 and 934, respectively; (aaaa) SEQ ID NOs: 847 and 935, respectively; (bbbb) SEQ ID NOs: 848 and 936, respectively; (cccc) SEQ ID NOs: 849 and 937, respectively; (dddd) SEQ ID NOs: 850 and 938, respectively; (eeee) SEQ ID NOs: 851 and 939, respectively; (ffff) SEQ ID NOs: 852 and 940, respectively; (gggg) SEQ ID NOs: 853 and 941, respectively; (hhhh) SEQ ID NOs: 854 and 942, respectively; (iiii) SEQ ID NOs: 855 and 943, respectively; and, (jjjj) SEQ ID NOs: 856 and 944, respectively.

Embodiment 77. The method of embodiment 76, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 786, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 874.

Embodiment 78. The method of embodiment 76, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 787, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 875.

Embodiment 79. The method of embodiment 76, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1537, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 929.

Embodiment 80. The method of embodiment 76, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 813, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 901.

Embodiment 81. A method for treating a subject having a disease, disorder or condition associated with NR1H3 expression, the method comprising administering to the subject a therapeutically effective amount of an RNAi oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and antisense strands comprise nucleotide sequences selected from the group consisting of:

(a) SEQ ID NOs: 945 and 1033, respectively; (b) SEQ ID NOs: 946 and 1034, respectively; (c) SEQ ID NOs: 947 and 1035, respectively; (d) SEQ ID NOs: 948 and 1036, respectively; (e) SEQ ID NOs: 949 and 1037, respectively; (f) SEQ ID NOs: 950 and 1038, respectively; (g) SEQ ID NOs: 951 and 1039, respectively; (h) SEQ ID NOs: 952 and 1040, respectively; (i) SEQ ID NOs: 953 and 1041, respectively; (j) SEQ ID NOs: 954 and 1042, respectively; (k) SEQ ID NOs: 955 and 1043, respectively; (l) SEQ ID NOs: 956 and 1044 respectively; (m) SEQ ID NOs: 957 and 1045, respectively; (n) SEQ ID NOs: 958 and 1046, respectively; (o) SEQ ID NOs: 959 and 1047, respectively; (p) SEQ ID NOs: 960 and 1048, respectively; (q) SEQ ID NOs: 961 and 1049, respectively; (r) SEQ ID NOs: 962 and 1050, respectively; (s) SEQ ID NOs: 963 and 1051, respectively; (t) SEQ ID NOs: 964 and 1052, respectively; (u) SEQ ID NOs: 965 and 1053, respectively; (v) SEQ ID NOs: 966 and 1054, respectively; (w) SEQ ID NOs: 967 and 1055, respectively; (x) SEQ ID NOs: 968 and 1056, respectively; (y) SEQ ID NOs: 969 and 1057, respectively; (z) SEQ ID NOs: 970 and 1058, respectively; (aa) SEQ ID NOs: 971 and 1059, respectively; (bb) SEQ ID NOs: 972 and 1060, respectively; (cc) SEQ ID NOs: 973 and 1061, respectively; (dd) SEQ ID NOs: 974 and 1062, respectively; (ee) SEQ ID NOs: 975 and 1063, respectively; (ff) SEQ ID NOs: 976 and 1064, respectively; (gg) SEQ ID NOs: 977 and 1065, respectively; (hh) SEQ ID NOs: 978 and 1066, respectively; (ii) SEQ ID NOs: 979 and 1067, respectively; (jj) SEQ ID NOs: 980 and 1068, respectively; (kk) SEQ ID NOs: 981 and 1069, respectively; (ll) SEQ ID NOs: 982 and 1070, respectively; (mm) SEQ ID NOs: 983 and 1071, respectively; (nn) SEQ ID NOs: 984 and 1072, respectively; (oo) SEQ ID NOs: 985 and 1073, respectively; (pp) SEQ ID NOs: 986 and 1074, respectively; (qq) SEQ ID NOs: 987 and 1075, respectively; (rr) SEQ ID NOs: 988 and 1076, respectively; (ss) SEQ ID NOs: 989 and 1077, respectively; (tt) SEQ ID NOs: 990 and 1078, respectively; (uu) SEQ ID NOs: 991 and 1079, respectively; (vv) SEQ ID NOs: 992 and 1080, respectively; (ww) SEQ ID NOs: 993 and 1081, respectively; (xx) SEQ ID NOs: 994 and 1082, respectively; (yy) SEQ ID NOs: 995 and 1083, respectively; (zz) SEQ ID NOs: 996 and 1084, respectively; (aaa) SEQ ID NOs: 997 and 1085, respectively; (bbb) SEQ ID NOs: 998 and 1086, respectively; (ccc) SEQ ID NOs: 999 and 1087, respectively; (ddd) SEQ ID NOs: 1000 and 1088, respectively; (eee) SEQ ID NOs: 1001 and 1089, respectively; (fff) SEQ ID NOs: 1002 and 1090, respectively; (ggg) SEQ ID NOs: 1003 and 1091, respectively; (hhh) SEQ ID NOs: 1004 and 1092 respectively; (iii) SEQ ID NOs: 1005 and 1093 respectively; (jjj) SEQ ID NOs: 1006 and 1094, respectively; (kkk) SEQ ID NOs: 1007 and 1095, respectively; (lll) SEQ ID NOs: 1008 and 1096, respectively; (mmm) SEQ ID NOs: 1009 and 1097, respectively; (nnn) SEQ ID NOs: 1010 and 1098, respectively; (ooo) SEQ ID NOs: 1011 and 1099, respectively; (ppp) SEQ ID NOs: 1012 and 1100, respectively; (qqq) SEQ ID NOs: 1013 and 1101, respectively; (rrr) SEQ ID NOs: 1014 and 1102 respectively; (sss) SEQ ID NOs: 1015 and 1103, respectively; (ttt) SEQ ID NOs: 1016 and 1104, respectively; (uuu) SEQ ID NOs: 1017 and 1105, respectively; (vvv) SEQ ID NOs: 1018 and 1106, respectively; (www) SEQ ID NOs: 1019 and 1107, respectively; (xxx) SEQ ID NOs: 1020 and 1108, respectively; (yyy) SEQ ID NOs: 1021 and 1109, respectively; (zzz) SEQ ID NOs: 1022 and 1110, respectively; (aaaa) SEQ ID NOs: 1023 and 1111, respectively; (bbbb) SEQ ID NOs: 1024 and 1112, respectively; (cccc) SEQ ID NOs: 1025 and 1113, respectively; (dddd) SEQ ID NOs: 1026 and 1114, respectively; (eeee) SEQ ID NOs: 1027 and 1115, respectively; (ffff) SEQ ID NOs: 1028 and 1116, respectively; (gggg) SEQ ID NOs: 1029 and 1117, respectively; (hhhh) SEQ ID NOs: 1030 and 1118, respectively; (iiii) SEQ ID NOs: 1031 and 1119, respectively, and; (jjjj) SEQ ID NOs: 1032 and 1120, respectively.

Embodiment 82. The method of embodiment 81, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 963, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1051.

Embodiment 83. The method of embodiment 81, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 964, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1052.

Embodiment 84. The method of embodiment 81, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1006, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1094.

Embodiment 85. The method of embodiment 81, wherein the sense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1018, wherein the antisense strand comprises a nucleotide sequence as set forth in SEQ ID NO: 1106.

Embodiment 86. The method of any one of embodiments 74 to 85, wherein the disease, disorder or condition associated with NR1H3 expression is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 87. Use of the RNAi oligonucleotide of any one of embodiments 1 to 65, or the pharmaceutical composition of embodiment 67, in the manufacture of a medicament for the treatment of a disease, disorder or condition associated with NR1H3 expression, optionally for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 88. The RNAi oligonucleotide of any one of embodiments 1 to 65, or the pharmaceutical composition of embodiment 67, for use, or adaptable for use, in the treatment of a disease, disorder or condition associated with NR1H3 expression, optionally for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 89. A kit comprising the RNAi oligonucleotide of any one of embodiments 1 to 65, an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration to a subject having a disease, disorder or condition associated with NR1H3 expression.

Embodiment 90. The use of embodiment 87, the RNAi oligonucleotide or pharmaceutical composition for use, or adaptable for use, of embodiment 88, or the kit of embodiment 89, wherein the disease, disorder or condition associated with NR1H3 expression is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus.

Embodiment 91. A double stranded RNAi oligonucleotide (dsRNAi) for reducing NR1H3 expression, the oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein

-   -   (i) the sense strand comprises a nucleotide sequence comprising         at least 15, 17, or 19 contiguous nucleotides, with 0, 1, 2, or         3 mismatches, of a portion of a nucleotide sequence of any one         of SEQ ID NOs: 1-384, SEQ ID NOs: 1125-1511, SEQ ID NOs:         769-856, SEQ ID NOs: 1519-1552 or SEQ ID NOs: 945-1032; and     -   (ii) the antisense strand comprises a nucleotide sequence         comprising at least 15, 17, or 19 contiguous nucleotides, with         0, 1, 2, or 3 mismatches, of a portion of a nucleotide sequence         of any one of SEQ ID NOs: 385-768, SEQ ID NOs 857-944, SEQ ID         NOs 1512-1515, or SEQ ID NOs: 1033-1120.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety.

SEQ Name Species Description Sequence ID NO NR1H3-764- Artificial 25 mer sense UGUCCUGUCAGAAGAACAGAUCC 1 784-861 Sequence strand GC NR1H3-766- Artificial 25 mer sense UCCUGUCAGAAGAACAGAUACGC 2 786-863 Sequence strand CU NR1H3-789- Artificial 25 mer sense CUGAAGAAACUGAAGCGGCAAG 3 809-886 Sequence strand AGG NR1H3-790- Artificial 25 mer sense UGAAGAAACUGAAGCGGCAAGA 4 810-887 Sequence strand GGA NR1H3-791- Artificial 25 mer sense GAAGAAACUGAAGCGGCAAAAG 5 811-888 Sequence strand GAG NR1H3-792- Artificial 25 mer sense AAGAAACUGAAGCGGCAAGAGG 6 812-889 Sequence strand AGG NR1H3-793- Artificial 25 mer sense AGAAACUGAAGCGGCAAGAAGA 7 813-890 Sequence strand GGA NR1H3-795- Artificial 25 mer sense AAACUGAAGCGGCAAGAGGAGG 8 815-892 Sequence strand AAC NR1H3-796- Artificial 25 mer sense AACUGAAGCGGCAAGAGGAAGA 9 816-893 Sequence strand ACA NR1H3-797- Artificial 25 mer sense ACUGAAGCGGCAAGAGGAGAAA 10 817-894 Sequence strand CAG NR1H3-798- Artificial 25 mer sense CUGAAGCGGCAAGAGGAGGAAC 11 818-895 Sequence strand AGG NR1H3-799- Artificial 25 mer sense UGAAGCGGCAAGAGGAGGAACA 12 819-896 Sequence strand GGC NR1H3-802- Artificial 25 mer sense AGCGGCAAGAGGAGGAACAAGC 13 822-899 Sequence strand UCA NR1H3-803- Artificial 25 mer sense GCGGCAAGAGGAGGAACAGACUC 14 823-900 Sequence strand AU NR1H3-804- Artificial 25 mer sense CGGCAAGAGGAGGAACAGGAUC 15 824-901 Sequence strand AUG NR1H3-806- Artificial 25 mer sense GCAAGAGGAGGAACAGGCUAAU 16 826-903 Sequence strand GCC NR1H3-808- Artificial 25 mer sense AAGAGGAGGAACAGGCUCAAGCC 17 828-905 Sequence strand AC NR1H3-809- Artificial 25 mer sense AGAGGAGGAACAGGCUCAUACCA 18 829-906 Sequence strand CA NR1H3-810- Artificial 25 mer sense GAGGAGGAACAGGCUCAUGACAC 19 830-907 Sequence strand AU NR1H3-811- Artificial 25 mer sense AGGAGGAACAGGCUCAUGCAACA 20 831-908 Sequence strand UC NR1H3-813- Artificial 25 mer sense GAGGAACAGGCUCAUGCCAAAUC 21 833-910 Sequence strand CU NR1H3-844 Artificial 25 mer sense CCAGGGCUUCCUCACCCCCACAA 22 Sequence strand AU NR1H3-895- Artificial 25 mer sense UGGGCAUGAUCGAGAAGCUAGU 23 915-992 Sequence strand CGC NR1H3-898- Artificial 25 mer sense GCAUGAUCGAGAAGCUCGUAGCU 24 918-995 Sequence strand GC NR1H3-915- Artificial 25 mer sense GUCGCUGCCCAGCAACAGUAUAA 25 935 Sequence strand CC NR1H3-917- Artificial 25 mer sense CGCUGCCCAGCAACAGUGUAACC 26 937 Sequence strand GG NR1H3-922- Artificial 25 mer sense CCCAGCAACAGUGUAACCGACGC 27 942 Sequence strand UC NR1H3-924- Artificial 25 mer sense CAGCAACAGUGUAACCGGCACUC 28 944 Sequence strand CU NR1H3-925- Artificial 25 mer sense AGCAACAGUGUAACCGGCGAUCC 29 945 Sequence strand UU NR1H3-927- Artificial 25 mer sense CAACAGUGUAACCGGCGCUACUU 30 947 Sequence strand UU NR1H3-928- Artificial 25 mer sense AACAGUGUAACCGGCGCUCAUUU 31 948 Sequence strand UC NR1H3-929- Artificial 25 mer sense ACAGUGUAACCGGCGCUCCAUUU 32 949 Sequence strand CU NR1H3-930- Artificial 25 mer sense CAGUGUAACCGGCGCUCCUAUUC 33 950 Sequence strand UG NR1H3-931- Artificial 25 mer sense AGUGUAACCGGCGCUCCUUAUCU 34 951 Sequence strand GA NR1H3-932- Artificial 25 mer sense GUGUAACCGGCGCUCCUUUACUG 35 952 Sequence strand AC NR1H3-933- Artificial 25 mer sense UGUAACCGGCGCUCCUUUUAUGA 36 953 Sequence strand CC NR1H3-941- Artificial 25 mer sense GCGCUCCUUUUCUGACCGGAUUC 37 961 Sequence strand GA NR1H3-944- Artificial 25 mer sense CUCCUUUUCUGACCGGCUUAGAG 38 964 Sequence strand UC NR1H3-945- Artificial 25 mer sense UCCUUUUCUGACCGGCUUCAAGU 39 965 Sequence strand CA NR1H3-946- Artificial 25 mer sense CCUUUUCUGACCGGCUUCGAGUC 40 966 Sequence strand AC NR1H3-947- Artificial 25 mer sense CUUUUCUGACCGGCUUCGAAUCA 41 967 Sequence strand CG NR1H3-949- Artificial 25 mer sense UUUCUGACCGGCUUCGAGUAACG 42 969 Sequence strand CC NR1H3-951- Artificial 25 mer sense UCUGACCGGCUUCGAGUCAAGCC 43 971 Sequence strand UU NR1H3-952- Artificial 25 mer sense CUGACCGGCUUCGAGUCACACCU 44 972 Sequence strand UG NR1H3-953- Artificial 25 mer sense UGACCGGCUUCGAGUCACGACUU 45 973 Sequence strand GG NR1H3-1151- Artificial 25 mer sense GGUGAUGCUUCUGGAGACAACUC 46 1171 Sequence strand GG NR1H3-1153- Artificial 25 mer sense UGAUGCUUCUGGAGACAUCACGG 47 1173 Sequence strand AG NR1H3-1154- Artificial 25 mer sense GAUGCUUCUGGAGACAUCUAGG 48 1174 Sequence strand AGG NR1H3-1155- Artificial 25 mer sense AUGCUUCUGGAGACAUCUCAGAG 49 1175 Sequence strand GU NR1H3-1156- Artificial 25 mer sense UGCUUCUGGAGACAUCUCGAAGG 50 1176 Sequence strand UA NR1H3-1157- Artificial 25 mer sense GCUUCUGGAGACAUCUCGGAGGU 51 1177 Sequence strand AC NR1H3-1158- Artificial 25 mer sense CUUCUGGAGACAUCUCGGAAGUA 52 1178 Sequence strand CA NR1H3-1159- Artificial 25 mer sense UUCUGGAGACAUCUCGGAGAUAC 53 1179 Sequence strand AA NR1H3-1160- Artificial 25 mer sense UCUGGAGACAUCUCGGAGGAACA 54 1180 Sequence strand AC NR1H3-1161- Artificial 25 mer sense CUGGAGACAUCUCGGAGGUACAA 55 1181 Sequence strand CC NR1H3-1162- Artificial 25 mer sense UGGAGACAUCUCGGAGGUAAAA 56 1182 Sequence strand CCC NR1H3-1163- Artificial 25 mer sense GGAGACAUCUCGGAGGUACAACC 57 1183 Sequence strand CU NR1H3-1164- Artificial 25 mer sense GAGACAUCUCGGAGGUACAACCC 58 1184 Sequence strand UG NR1H3-1165- Artificial 25 mer sense AGACAUCUCGGAGGUACAAACCU 59 1185 Sequence strand GG NR1H3-1166- Artificial 25 mer sense GACAUCUCGGAGGUACAACACUG 60 1186 Sequence strand GG NR1H3-1167- Artificial 25 mer sense ACAUCUCGGAGGUACAACCAUGG 61 1187 Sequence strand GA NR1H3-1169- Artificial 25 mer sense AUCUCGGAGGUACAACCCUAGGA 62 1189 Sequence strand GU NR1H3-1170- Artificial 25 mer sense UCUCGGAGGUACAACCCUGAGAG 63 1190 Sequence strand UG NR1H3-1171- Artificial 25 mer sense CUCGGAGGUACAACCCUGGAAGU 64 1191 Sequence strand GA NR1H3-1173- Artificial 25 mer sense CGGAGGUACAACCCUGGGAAUGA 65 1193 Sequence strand GA NR1H3-1175- Artificial 25 mer sense GAGGUACAACCCUGGGAGUAAG 66 1195 Sequence strand AGU NR1H3-1176- Artificial 25 mer sense AGGUACAACCCUGGGAGUGAGA 67 1196 Sequence strand GUA NR1H3-1177- Artificial 25 mer sense GGUACAACCCUGGGAGUGAAAG 68 1197 Sequence strand UAU NR1H3-1178- Artificial 25 mer sense GUACAACCCUGGGAGUGAGAGU 69 1198 Sequence strand AUC NR1H3-1179- Artificial 25 mer sense UACAACCCUGGGAGUGAGAAUA 70 1199 Sequence strand UCA NR1H3-1180- Artificial 25 mer sense ACAACCCUGGGAGUGAGAGAAUC 71 1200 Sequence strand AC NR1H3-1181- Artificial 25 mer sense CAACCCUGGGAGUGAGAGUAUCA 72 1201 Sequence strand CC NR1H3-1182- Artificial 25 mer sense AACCCUGGGAGUGAGAGUAACAC 73 1202 Sequence strand CU NR1H3-1183- Artificial 25 mer sense ACCCUGGGAGUGAGAGUAUAACC 74 1203 Sequence strand UU NR1H3-1184- Artificial 25 mer sense CCCUGGGAGUGAGAGUAUCACCU 75 1204 Sequence strand UC NR1H3-1185- Artificial 25 mer sense CCUGGGAGUGAGAGUAUCAACU 76 1205 Sequence strand UCC NR1H3-1186- Artificial 25 mer sense CUGGGAGUGAGAGUAUCACAUU 77 1206 Sequence strand CCU NR1H3-1187- Artificial 25 mer sense UGGGAGUGAGAGUAUCACCAUCC 78 1207 Sequence strand UC NR1H3-1188- Artificial 25 mer sense GGGAGUGAGAGUAUCACCUACCU 79 1208 Sequence strand CA NR1H3-1190- Artificial 25 mer sense GAGUGAGAGUAUCACCUUCAUCA 80 1210 Sequence strand AG NR1H3-1191- Artificial 25 mer sense AGUGAGAGUAUCACCUUCCACAA 81 1211 Sequence strand GG NR1H3-1192- Artificial 25 mer sense GUGAGAGUAUCACCUUCCUAAAG 82 1212 Sequence strand GA NR1H3-1193- Artificial 25 mer sense UGAGAGUAUCACCUUCCUCAAGG 83 1213 Sequence strand AU NR1H3-1194- Artificial 25 mer sense GAGAGUAUCACCUUCCUCAAGGA 84 1214 Sequence strand UU NR1H3-1196- Artificial 25 mer sense GAGUAUCACCUUCCUCAAGAAUU 85 1216 Sequence strand UC NR1H3-1197- Artificial 25 mer sense AGUAUCACCUUCCUCAAGGAUUU 86 1217 Sequence strand CA NR1H3-1198- Artificial 25 mer sense GUAUCACCUUCCUCAAGGAAUUC 87 1218 Sequence strand AG NR1H3-1199- Artificial 25 mer sense UAUCACCUUCCUCAAGGAUAUCA 88 1219 Sequence strand GU NR1H3-1200- Artificial 25 mer sense AUCACCUUCCUCAAGGAUUACAG 89 1220 Sequence strand UU NR1H3-1203- Artificial 25 mer sense ACCUUCCUCAAGGAUUUCAAUUA 90 1223 Sequence strand UA NR1H3-1204- Artificial 25 mer sense CCUUCCUCAAGGAUUUCAGAUAU 91 1224 Sequence strand AA NR1H3-1207- Artificial 25 mer sense UCCUCAAGGAUUUCAGUUAAAAC 92 1227 Sequence strand CG NR1H3-1211- Artificial 25 mer sense CAAGGAUUUCAGUUAUAACAGG 93 1231 Sequence strand GAA NR1H3-1212- Artificial 25 mer sense AAGGAUUUCAGUUAUAACCAGG 94 1232 Sequence strand AAG NR1H3-1213- Artificial 25 mer sense AGGAUUUCAGUUAUAACCGAGA 95 1233 Sequence strand AGA NR1H3-1214- Artificial 25 mer sense GGAUUUCAGUUAUAACCGGAAA 96 1234 Sequence strand GAC NR1H3-1215- Artificial 25 mer sense GAUUUCAGUUAUAACCGGGAAG 97 1235 Sequence strand ACU NR1H3-1216- Artificial 25 mer sense AUUUCAGUUAUAACCGGGAAGA 98 1236 Sequence strand CUU NR1H3-1217- Artificial 25 mer sense UUUCAGUUAUAACCGGGAAAAC 99 1237 Sequence strand UUU NR1H3-1218- Artificial 25 mer sense UUCAGUUAUAACCGGGAAGACU 100 1238 Sequence strand UUG NR1H3-1219- Artificial 25 mer sense UCAGUUAUAACCGGGAAGAAUU 101 1239 Sequence strand UGC NR1H3-1220- Artificial 25 mer sense CAGUUAUAACCGGGAAGACAUU 102 1240 Sequence strand GCC NR1H3-1222- Artificial 25 mer sense GUUAUAACCGGGAAGACUUAGCC 103 1242 Sequence strand AA NR1H3-1223- Artificial 25 mer sense UUAUAACCGGGAAGACUUUACCA 104 1243 Sequence strand AA NR1H3-1224- Artificial 25 mer sense UAUAACCGGGAAGACUUUGACA 105 1244 Sequence strand AAG NR1H3-1225- Artificial 25 mer sense AUAACCGGGAAGACUUUGCAAA 106 1245 Sequence strand AGC NR1H3-1226- Artificial 25 mer sense UAACCGGGAAGACUUUGCCAAAG 107 1246 Sequence strand CA NR1H3-1227- Artificial 25 mer sense AACCGGGAAGACUUUGCCAAAGC 108 1247 Sequence strand AG NR1H3-1228- Artificial 25 mer sense ACCGGGAAGACUUUGCCAAAGCA 109 1248 Sequence strand GG NR1H3-1229- Artificial 25 mer sense CCGGGAAGACUUUGCCAAAACAG 110 1249 Sequence strand GG NR1H3-1232- Artificial 25 mer sense GGAAGACUUUGCCAAAGCAAGGC 111 1252 Sequence strand UG NR1H3-1233- Artificial 25 mer sense GAAGACUUUGCCAAAGCAGAGCU 112 1253 Sequence strand GC NR1H3-1234- Artificial 25 mer sense AAGACUUUGCCAAAGCAGGACUG 113 1254 Sequence strand CA NR1H3-1235- Artificial 25 mer sense AGACUUUGCCAAAGCAGGGAUGC 114 1255 Sequence strand AA NR1H3-1236- Artificial 25 mer sense GACUUUGCCAAAGCAGGGCAGCA 115 1256 Sequence strand AG NR1H3-1237- Artificial 25 mer sense ACUUUGCCAAAGCAGGGCUACAA 116 1257 Sequence strand GU NR1H3-1238- Artificial 25 mer sense CUUUGCCAAAGCAGGGCUGAAAG 117 1258 Sequence strand UG NR1H3-1241- Artificial 25 mer sense UGCCAAAGCAGGGCUGCAAAUGG 118 1261 Sequence strand AA NR1H3-1242- Artificial 25 mer sense GCCAAAGCAGGGCUGCAAGAGGA 119 1262 Sequence strand AU NR1H3-1243- Artificial 25 mer sense CCAAAGCAGGGCUGCAAGUAGAA 120 1263 Sequence strand UU NR1H3-1244- Artificial 25 mer sense CAAAGCAGGGCUGCAAGUGAAA 121 1264 Sequence strand UUC NR1H3-1245- Artificial 25 mer sense AAAGCAGGGCUGCAAGUGGAAU 122 1265 Sequence strand UCA NR1H3-1246- Artificial 25 mer sense AAGCAGGGCUGCAAGUGGAAUU 123 1266 Sequence strand CAU NR1H3-1247- Artificial 25 mer sense AGCAGGGCUGCAAGUGGAAAUC 124 1267 Sequence strand AUC NR1H3-1248- Artificial 25 mer sense GCAGGGCUGCAAGUGGAAUACA 125 1268 Sequence strand UCA NR1H3-1250- Artificial 25 mer sense AGGGCUGCAAGUGGAAUUCAUC 126 1270 Sequence strand AAC NR1H3-1251- Artificial 25 mer sense GGGCUGCAAGUGGAAUUCAACA 127 1271 Sequence strand ACC NR1H3-1252- Artificial 25 mer sense GGCUGCAAGUGGAAUUCAUAAA 128 1272 Sequence strand CCC NR1H3-1253- Artificial 25 mer sense GCUGCAAGUGGAAUUCAUCAACC 129 1273 Sequence strand CC NR1H3-1256- Artificial 25 mer sense GCAAGUGGAAUUCAUCAACACCA 130 1276 Sequence strand UC NR1H3-1258- Artificial 25 mer sense AAGUGGAAUUCAUCAACCCAAUC 131 1278 Sequence strand UU NR1H3-1259- Artificial 25 mer sense AGUGGAAUUCAUCAACCCCAUCU 132 1279 Sequence strand UC NR1H3-1261- Artificial 25 mer sense UGGAAUUCAUCAACCCCAUAUUC 133 1281 Sequence strand GA NR1H3-1262- Artificial 25 mer sense GGAAUUCAUCAACCCCAUCAUCG 134 1282 Sequence strand AG NR1H3-1265- Artificial 25 mer sense AUUCAUCAACCCCAUCUUCAAGU 135 1285 Sequence strand UC NR1H3-1266- Artificial 25 mer sense UUCAUCAACCCCAUCUUCGAGUU 136 1286 Sequence strand CU NR1H3-1267- Artificial 25 mer sense UCAUCAACCCCAUCUUCGAAUUC 137 1287 Sequence strand UC NR1H3-1268- Artificial 25 mer sense CAUCAACCCCAUCUUCGAGAUCU 138 1288 Sequence strand CC NR1H3-1269- Artificial 25 mer sense AUCAACCCCAUCUUCGAGUACUC 139 1289 Sequence strand CA NR1H3-1270- Artificial 25 mer sense UCAACCCCAUCUUCGAGUUAUCC 140 1290 Sequence strand AG NR1H3-1271- Artificial 25 mer sense CAACCCCAUCUUCGAGUUCACCA 141 1291 Sequence strand GG NR1H3-1272- Artificial 25 mer sense AACCCCAUCUUCGAGUUCUACAG 142 1292 Sequence strand GG NR1H3-1273- Artificial 25 mer sense ACCCCAUCUUCGAGUUCUCAAGG 143 1293 Sequence strand GC NR1H3-1275- Artificial 25 mer sense CCCAUCUUCGAGUUCUCCAAGGC 144 1295 Sequence strand CA NR1H3-1276- Artificial 25 mer sense CCAUCUUCGAGUUCUCCAGAGCC 145 1296 Sequence strand AU NR1H3-1277- Artificial 25 mer sense CAUCUUCGAGUUCUCCAGGACCA 146 1297 Sequence strand UG NR1H3-1278- Artificial 25 mer sense AUCUUCGAGUUCUCCAGGGACAU 147 1298 Sequence strand GA NR1H3-1279- Artificial 25 mer sense UCUUCGAGUUCUCCAGGGCAAUG 148 1299 Sequence strand AA NR1H3-1280- Artificial 25 mer sense CUUCGAGUUCUCCAGGGCCAUGA 149 1300 Sequence strand AU NR1H3-1281- Artificial 25 mer sense UUCGAGUUCUCCAGGGCCAAGAA 150 1301 Sequence strand UG NR1H3-1282- Artificial 25 mer sense UCGAGUUCUCCAGGGCCAUAAAU 151 1302 Sequence strand GA NR1H3-1283- Artificial 25 mer sense CGAGUUCUCCAGGGCCAUGAAUG 152 1303 Sequence strand AG NR1H3-1284- Artificial 25 mer sense GAGUUCUCCAGGGCCAUGAAUGA 153 1304 Sequence strand GC NR1H3-1285- Artificial 25 mer sense AGUUCUCCAGGGCCAUGAAAGAG 154 1305 Sequence strand CU NR1H3-1286- Artificial 25 mer sense GUUCUCCAGGGCCAUGAAUAAGC 155 1306 Sequence strand UG NR1H3-1288- Artificial 25 mer sense UCUCCAGGGCCAUGAAUGAACUG 156 1308 Sequence strand CA NR1H3-1289- Artificial 25 mer sense CUCCAGGGCCAUGAAUGAGAUGC 157 1309 Sequence strand AA NR1H3-1290- Artificial 25 mer sense UCCAGGGCCAUGAAUGAGCAGCA 158 1310 Sequence strand AC NR1H3-1291- Artificial 25 mer sense CCAGGGCCAUGAAUGAGCUACAA 159 1311 Sequence strand CU NR1H3-1292- Artificial 25 mer sense CAGGGCCAUGAAUGAGCUGAAAC 160 1312 Sequence strand UC NR1H3-1293- Artificial 25 mer sense AGGGCCAUGAAUGAGCUGCAACU 161 1313 Sequence strand CA NR1H3-1294- Artificial 25 mer sense GGGCCAUGAAUGAGCUGCAACUC 162 1314 Sequence strand AA NR1H3-1295- Artificial 25 mer sense GGCCAUGAAUGAGCUGCAAAUCA 163 1315 Sequence strand AU NR1H3-1296- Artificial 25 mer sense GCCAUGAAUGAGCUGCAACACAA 164 1316 Sequence strand UG NR1H3-1297- Artificial 25 mer sense CCAUGAAUGAGCUGCAACUAAAU 165 1317 Sequence strand GA NR1H3-1338- Artificial 25 mer sense CUCAUUGCUAUCAGCAUCUACUC 166 1358 Sequence strand UG NR1H3-1339- Artificial 25 mer sense UCAUUGCUAUCAGCAUCUUAUCU 167 1359 Sequence strand GC NR1H3-1340- Artificial 25 mer sense CAUUGCUAUCAGCAUCUUCACUG 168 1360 Sequence strand CA NR1H3-1341- Artificial 25 mer sense AUUGCUAUCAGCAUCUUCUAUGC 169 1361 Sequence strand AG NR1H3-1342- Artificial 25 mer sense UUGCUAUCAGCAUCUUCUCAGCA 170 1362 Sequence strand GA NR1H3-1343- Artificial 25 mer sense UGCUAUCAGCAUCUUCUCUACAG 171 1363 Sequence strand AC NR1H3-1344- Artificial 25 mer sense GCUAUCAGCAUCUUCUCUGAAGA 172 1364 Sequence strand CC NR1H3-1345- Artificial 25 mer sense CUAUCAGCAUCUUCUCUGCAGAC 173 1365 Sequence strand CG NR1H3-1346- Artificial 25 mer sense UAUCAGCAUCUUCUCUGCAAACC 174 1366 Sequence strand GG NR1H3-1347- Artificial 25 mer sense AUCAGCAUCUUCUCUGCAGACCG 175 1367 Sequence strand GC NR1H3-1377- Artificial 25 mer sense GUGCAGGACCAGCUCCAGGAAGA 176 1443 Sequence strand GA NR1H3-1379- Artificial 25 mer sense GCAGGACCAGCUCCAGGUAAAGA 177 1445 Sequence strand GG NR1H3-1383- Artificial 25 mer sense GACCAGCUCCAGGUAGAGAAGCU 178 1449 Sequence strand GC NR1H3-1384- Artificial 25 mer sense ACCAGCUCCAGGUAGAGAGACUG 179 1450 Sequence strand CA NR1H3-1385- Artificial 25 mer sense CCAGCUCCAGGUAGAGAGGAUGC 180 1451 Sequence strand AG NR1H3-1387- Artificial 25 mer sense AGCUCCAGGUAGAGAGGCUACAG 181 1453 Sequence strand CA NR1H3-1388- Artificial 25 mer sense GCUCCAGGUAGAGAGGCUGAAGC 182 1454 Sequence strand AC NR1H3-1391- Artificial 25 mer sense CCAGGUAGAGAGGCUGCAGAACA 183 1457 Sequence strand CA NR1H3-1393- Artificial 25 mer sense AGGUAGAGAGGCUGCAGCAAAC 184 1459 Sequence strand AUA NR1H3-1394- Artificial 25 mer sense GGUAGAGAGGCUGCAGCACACAU 185 1460 Sequence strand AU NR1H3-1395- Artificial 25 mer sense GUAGAGAGGCUGCAGCACAAAU 186 1461 Sequence strand AUG NR1H3-1396- Artificial 25 mer sense UAGAGAGGCUGCAGCACACAUAU 187 1462 Sequence strand GU NR1H3-1397- Artificial 25 mer sense AGAGAGGCUGCAGCACACAAAUG 188 1463 Sequence strand UG NR1H3-1398- Artificial 25 mer sense GAGAGGCUGCAGCACACAUAUGU 189 1464 Sequence strand GG NR1H3-1399- Artificial 25 mer sense AGAGGCUGCAGCACACAUAAGUG 190 1465 Sequence strand GA NR1H3-1400- Artificial 25 mer sense GAGGCUGCAGCACACAUAUAUGG 191 1466 Sequence strand AA NR1H3-1401- Artificial 25 mer sense AGGCUGCAGCACACAUAUGAGGA 192 1467 Sequence strand AG NR1H3-1402- Artificial 25 mer sense GGCUGCAGCACACAUAUGUAGAA 193 1468 Sequence strand GC NR1H3-1403- Artificial 25 mer sense GCUGCAGCACACAUAUGUGAAAG 194 1469 Sequence strand CC NR1H3-1404- Artificial 25 mer sense CUGCAGCACACAUAUGUGGAAGC 195 1470 Sequence strand CC NR1H3-1406- Artificial 25 mer sense GCAGCACACAUAUGUGGAAACCC 196 1472 Sequence strand UG NR1H3-1407- Artificial 25 mer sense CAGCACACAUAUGUGGAAGACCU 197 1473 Sequence strand GC NR1H3-1408- Artificial 25 mer sense AGCACACAUAUGUGGAAGCACUG 198 1474 Sequence strand CA NR1H3-1410- Artificial 25 mer sense CACACAUAUGUGGAAGCCCAGCA 199 1476 Sequence strand UG NR1H3-1411- Artificial 25 mer sense ACACAUAUGUGGAAGCCCUACAU 200 1477 Sequence strand GC NR1H3-1412- Artificial 25 mer sense CACAUAUGUGGAAGCCCUGAAUG 201 1478 Sequence strand CC NR1H3-1413- Artificial 25 mer sense ACAUAUGUGGAAGCCCUGCAUGC 202 1479 Sequence strand CU NR1H3-1414- Artificial 25 mer sense CAUAUGUGGAAGCCCUGCAAGCC 203 1480 Sequence strand UA NR1H3-1415- Artificial 25 mer sense AUAUGUGGAAGCCCUGCAUACCU 204 1481 Sequence strand AC NR1H3-1416- Artificial 25 mer sense UAUGUGGAAGCCCUGCAUGACUA 205 1482 Sequence strand CG NR1H3-1417- Artificial 25 mer sense AUGUGGAAGCCCUGCAUGCAUAC 206 1483 Sequence strand GU NR1H3-1418- Artificial 25 mer sense UGUGGAAGCCCUGCAUGCCAACG 207 1484 Sequence strand UC NR1H3-1419- Artificial 25 mer sense GUGGAAGCCCUGCAUGCCUACGU 208 1485 Sequence strand CU NR1H3-1420- Artificial 25 mer sense UGGAAGCCCUGCAUGCCUAAGUC 209 1486 Sequence strand UC NR1H3-1421- Artificial 25 mer sense GGAAGCCCUGCAUGCCUACAUCU 210 1487 Sequence strand CC NR1H3-1422- Artificial 25 mer sense GAAGCCCUGCAUGCCUACGACUC 211 1488 Sequence strand CA NR1H3-1423- Artificial 25 mer sense AAGCCCUGCAUGCCUACGUAUCC 212 1489 Sequence strand AU NR1H3-1424- Artificial 25 mer sense AGCCCUGCAUGCCUACGUCACCA 213 1490 Sequence strand UC NR1H3-1425- Artificial 25 mer sense GCCCUGCAUGCCUACGUCUACAU 214 1491 Sequence strand CC NR1H3-1426- Artificial 25 mer sense CCCUGCAUGCCUACGUCUCAAUC 215 1492 Sequence strand CA NR1H3-1427- Artificial 25 mer sense CCUGCAUGCCUACGUCUCCAUCC 216 1493 Sequence strand AC NR1H3-1428- Artificial 25 mer sense CUGCAUGCCUACGUCUCCAACCA 217 1494 Sequence strand CC NR1H3-1429- Artificial 25 mer sense UGCAUGCCUACGUCUCCAUACAC 218 1495 Sequence strand CA NR1H3-1430- Artificial 25 mer sense GCAUGCCUACGUCUCCAUCAACC 219 1496 Sequence strand AU NR1H3-1431- Artificial 25 mer sense CAUGCCUACGUCUCCAUCCACCA 220 1497 Sequence strand UC NR1H3-1432- Artificial 25 mer sense AUGCCUACGUCUCCAUCCAACAU 221 1498 Sequence strand CC NR1H3-1433- Artificial 25 mer sense UGCCUACGUCUCCAUCCACAAUC 222 1499 Sequence strand CC NR1H3-1434- Artificial 25 mer sense GCCUACGUCUCCAUCCACCAUCC 223 1500 Sequence strand CC NR1H3-1435- Artificial 25 mer sense CCUACGUCUCCAUCCACCAACCC 224 1501 Sequence strand CA NR1H3-1436- Artificial 25 mer sense CUACGUCUCCAUCCACCAUACCC 225 1502 Sequence strand AU NR1H3-1437- Artificial 25 mer sense UACGUCUCCAUCCACCAUCACCA 226 1503 Sequence strand UG NR1H3-1438- Artificial 25 mer sense ACGUCUCCAUCCACCAUCCACAU 227 1504 Sequence strand GA NR1H3-1439- Artificial 25 mer sense CGUCUCCAUCCACCAUCCCAAUG 228 1505 Sequence strand AC NR1H3-1440- Artificial 25 mer sense GUCUCCAUCCACCAUCCCCAUGA 229 1506 Sequence strand CC NR1H3-1442- Artificial 25 mer sense CUCCAUCCACCAUCCCCAUAACC 230 1508 Sequence strand GA NR1H3-1443- Artificial 25 mer sense UCCAUCCACCAUCCCCAUGACCG 231 1509 Sequence strand AC NR1H3-1444- Artificial 25 mer sense CCAUCCACCAUCCCCAUGAACGA 232 1510 Sequence strand CU NR1H3-1445- Artificial 25 mer sense CAUCCACCAUCCCCAUGACAGAC 233 1511 Sequence strand UG NR1H3-1446- Artificial 25 mer sense AUCCACCAUCCCCAUGACCAACU 234 1512 Sequence strand GA NR1H3-1447- Artificial 25 mer sense UCCACCAUCCCCAUGACCGACUG 235 1513 Sequence strand AU NR1H3-1448- Artificial 25 mer sense CCACCAUCCCCAUGACCGAAUGA 236 1514 Sequence strand UG NR1H3-1449- Artificial 25 mer sense CACCAUCCCCAUGACCGACAGAU 237 1515 Sequence strand GU NR1H3-1450- Artificial 25 mer sense ACCAUCCCCAUGACCGACUAAUG 238 1516 Sequence strand UU NR1H3-1451- Artificial 25 mer sense CCAUCCCCAUGACCGACUGAUGU 239 1517 Sequence strand UC NR1H3-1452- Artificial 25 mer sense CAUCCCCAUGACCGACUGAAGUU 240 1518 Sequence strand CC NR1H3-1453- Artificial 25 mer sense AUCCCCAUGACCGACUGAUAUUC 241 1519 Sequence strand CC NR1H3-1454- Artificial 25 mer sense UCCCCAUGACCGACUGAUGAUCC 242 1520 Sequence strand CA NR1H3-1455- Artificial 25 mer sense CCCCAUGACCGACUGAUGUACCC 243 1521 Sequence strand AC NR1H3-1456- Artificial 25 mer sense CCCAUGACCGACUGAUGUUACCA 244 1522 Sequence strand CG NR1H3-1457- Artificial 25 mer sense CCAUGACCGACUGAUGUUCACAC 245 1523 Sequence strand GG NR1H3-1459- Artificial 25 mer sense AUGACCGACUGAUGUUCCCACGG 246 1525 Sequence strand AU NR1H3-1460- Artificial 25 mer sense UGACCGACUGAUGUUCCCAAGGA 247 1526 Sequence strand UG NR1H3-1461- Artificial 25 mer sense GACCGACUGAUGUUCCCACAGAU 248 1527 Sequence strand GC NR1H3-1462- Artificial 25 mer sense ACCGACUGAUGUUCCCACGAAUG 249 1528 Sequence strand CU NR1H3-1463- Artificial 25 mer sense CCGACUGAUGUUCCCACGGAUGC 250 1529 Sequence strand UA NR1H3-1465- Artificial 25 mer sense GACUGAUGUUCCCACGGAUACUA 251 1531 Sequence strand AU NR1H3-1466- Artificial 25 mer sense ACUGAUGUUCCCACGGAUGAUAA 252 1532 Sequence strand UG NR1H3-1468- Artificial 25 mer sense UGAUGUUCCCACGGAUGCUAAUG 253 1534 Sequence strand AA NR1H3-1469- Artificial 25 mer sense GAUGUUCCCACGGAUGCUAAUGA 254 1535 Sequence strand AA NR1H3-1471- Artificial 25 mer sense UGUUCCCACGGAUGCUAAUAAAA 255 1537 Sequence strand CU NR1H3-1472- Artificial 25 mer sense GUUCCCACGGAUGCUAAUGAAAC 256 1538 Sequence strand UG NR1H3-1473- Artificial 25 mer sense UUCCCACGGAUGCUAAUGAAACU 257 1539 Sequence strand GG NR1H3-1474- Artificial 25 mer sense UCCCACGGAUGCUAAUGAAACUG 258 1540 Sequence strand GU NR1H3-1475- Artificial 25 mer sense CCCACGGAUGCUAAUGAAAAUGG 259 1541 Sequence strand UG NR1H3-1476- Artificial 25 mer sense CCACGGAUGCUAAUGAAACAGGU 260 1542 Sequence strand GA NR1H3-1477- Artificial 25 mer sense CACGGAUGCUAAUGAAACUAGU 261 1543 Sequence strand GAG NR1H3-1478- Artificial 25 mer sense ACGGAUGCUAAUGAAACUGAUG 262 1544 Sequence strand AGC NR1H3-1479- Artificial 25 mer sense CGGAUGCUAAUGAAACUGGAGA 263 1545 Sequence strand GCC NR1H3-1480- Artificial 25 mer sense GGAUGCUAAUGAAACUGGUAAG 264 1546 Sequence strand CCU NR1H3-1481- Artificial 25 mer sense GAUGCUAAUGAAACUGGUGAGC 265 1547 Sequence strand CUC NR1H3-1483- Artificial 25 mer sense UGCUAAUGAAACUGGUGAGACU 266 1549 Sequence strand CCG NR1H3-1484- Artificial 25 mer sense GCUAAUGAAACUGGUGAGCAUCC 267 1550 Sequence strand GG NR1H3-1485- Artificial 25 mer sense CUAAUGAAACUGGUGAGCCACCG 268 1551 Sequence strand GA NR1H3-1486- Artificial 25 mer sense UAAUGAAACUGGUGAGCCUACG 269 1552 Sequence strand GAC NR1H3-1487- Artificial 25 mer sense AAUGAAACUGGUGAGCCUCAGG 270 1553 Sequence strand ACC NR1H3-1488- Artificial 25 mer sense AUGAAACUGGUGAGCCUCCAGAC 271 1554 Sequence strand CC NR1H3-1489- Artificial 25 mer sense UGAAACUGGUGAGCCUCCGAACC 272 1555 Sequence strand CU NR1H3-1491- Artificial 25 mer sense AAACUGGUGAGCCUCCGGAACCU 273 1557 Sequence strand GA NR1H3-1492- Artificial 25 mer sense AACUGGUGAGCCUCCGGACACUG 274 1558 Sequence strand AG NR1H3-1494- Artificial 25 mer sense CUGGUGAGCCUCCGGACCCAGAG 275 1560 Sequence strand CA NR1H3-1505- Artificial 25 mer sense CCGGACCCUGAGCAGCGUCAACU 276 1571 Sequence strand CA NR1H3-1507- Artificial 25 mer sense GGACCCUGAGCAGCGUCCAAUCA 277 1573 Sequence strand GA NR1H3-1508- Artificial 25 mer sense GACCCUGAGCAGCGUCCACACAG 278 1574 Sequence strand AG NR1H3-1509- Artificial 25 mer sense ACCCUGAGCAGCGUCCACUAAGA 279 1575 Sequence strand GC NR1H3-1510- Artificial 25 mer sense CCCUGAGCAGCGUCCACUCAGAG 280 1576 Sequence strand CA NR1H3-1511- Artificial 25 mer sense CCUGAGCAGCGUCCACUCAAAGC 281 1577 Sequence strand AA NR1H3-1512- Artificial 25 mer sense CUGAGCAGCGUCCACUCAGAGCA 282 1578 Sequence strand AG NR1H3-1513- Artificial 25 mer sense UGAGCAGCGUCCACUCAGAACAA 283 1579 Sequence strand GU NR1H3-1514- Artificial 25 mer sense GAGCAGCGUCCACUCAGAGAAAG 284 1580 Sequence strand UG NR1H3-1515- Artificial 25 mer sense AGCAGCGUCCACUCAGAGCAAGU 285 1581 Sequence strand GU NR1H3-1516- Artificial 25 mer sense GCAGCGUCCACUCAGAGCAAGUG 286 1582 Sequence strand UU NR1H3-1517- Artificial 25 mer sense CAGCGUCCACUCAGAGCAAAUGU 287 1583 Sequence strand UU NR1H3-1518- Artificial 25 mer sense AGCGUCCACUCAGAGCAAGAGUU 288 1584 Sequence strand UG NR1H3-1519- Artificial 25 mer sense GCGUCCACUCAGAGCAAGUAUUU 289 1585 Sequence strand GC NR1H3-1520- Artificial 25 mer sense CGUCCACUCAGAGCAAGUGAUUG 290 1586 Sequence strand CA NR1H3-1521- Artificial 25 mer sense GUCCACUCAGAGCAAGUGUAUGC 291 1587 Sequence strand AC NR1H3-1522- Artificial 25 mer sense UCCACUCAGAGCAAGUGUUAGCA 292 1588 Sequence strand CU NR1H3-1523- Artificial 25 mer sense CCACUCAGAGCAAGUGUUUACAC 293 1589 Sequence strand UG NR1H3-1525- Artificial 25 mer sense ACUCAGAGCAAGUGUUUGCACUG 294 1591 Sequence strand CG NR1H3-1526- Artificial 25 mer sense CUCAGAGCAAGUGUUUGCAAUGC 295 1592 Sequence strand GU NR1H3-1527- Artificial 25 mer sense UCAGAGCAAGUGUUUGCACAGCG 296 1593 Sequence strand UC NR1H3-1528- Artificial 25 mer sense CAGAGCAAGUGUUUGCACUACGU 297 1594 Sequence strand CU NR1H3-1529- Artificial 25 mer sense AGAGCAAGUGUUUGCACUGAGU 298 1595 Sequence strand CUG NR1H3-1530- Artificial 25 mer sense GAGCAAGUGUUUGCACUGCAUCU 299 1596 Sequence strand GC NR1H3-1531- Artificial 25 mer sense AGCAAGUGUUUGCACUGCGACUG 300 1597 Sequence strand CA NR1H3-1532- Artificial 25 mer sense GCAAGUGUUUGCACUGCGUAUGC 301 1598 Sequence strand AGA NR1H3-1533- Artificial 25 mer sense CAAGUGUUUGCACUGCGUCAGC 302 1599 Sequence strand GG NR1H3-1534- Artificial 25 mer sense AAGUGUUUGCACUGCGUCUACAG 303 1600 Sequence strand GA NR1H3-1535- Artificial 25 mer sense AGUGUUUGCACUGCGUCUGAAG 304 1601 Sequence strand GAC NR1H3-1536- Artificial 25 mer sense GUGUUUGCACUGCGUCUGCAGGA 305 1602 Sequence strand CA NR1H3-1537- Artificial 25 mer sense UGUUUGCACUGCGUCUGCAAGAC 306 1603 Sequence strand AA NR1H3-1538- Artificial 25 mer sense GUUUGCACUGCGUCUGCAGAACA 307 1604 Sequence strand AA NR1H3-1539- Artificial 25 mer sense UUUGCACUGCGUCUGCAGGACAA 308 1605 Sequence strand AA NR1H3-1540- Artificial 25 mer sense UUGCACUGCGUCUGCAGGAAAAA 309 1606 Sequence strand AA NR1H3-1541- Artificial 25 mer sense UGCACUGCGUCUGCAGGACAAAA 310 1607 Sequence strand AG NR1H3-1542- Artificial 25 mer sense GCACUGCGUCUGCAGGACAAAAA 311 1608 Sequence strand GC NR1H3-1543- Artificial 25 mer sense CACUGCGUCUGCAGGACAAAAAG 312 1609 Sequence strand CU NR1H3-1544- Artificial 25 mer sense ACUGCGUCUGCAGGACAAAAAGC 313 1610 Sequence strand UC NR1H3-1545- Artificial 25 mer sense CUGCGUCUGCAGGACAAAAAGCU 314 1611 Sequence strand CC NR1H3-1546- Artificial 25 mer sense UGCGUCUGCAGGACAAAAAACUC 315 1612 Sequence strand CC NR1H3-1547- Artificial 25 mer sense GCGUCUGCAGGACAAAAAGAUCC 316 1613 Sequence strand CA NR1H3-1548- Artificial 25 mer sense CGUCUGCAGGACAAAAAGCACCC 317 1614 Sequence strand AC NR1H3-1549- Artificial 25 mer sense GUCUGCAGGACAAAAAGCUACCA 318 1615 Sequence strand CC NR1H3-1550- Artificial 25 mer sense UCUGCAGGACAAAAAGCUCACAC 319 1616 Sequence strand CG NR1H3-1551- Artificial 25 mer sense CUGCAGGACAAAAAGCUCCAACC 320 1617 Sequence strand GC NR1H3-1553- Artificial 25 mer sense GCAGGACAAAAAGCUCCCAACGC 321 1619 Sequence strand UG NR1H3-1554- Artificial 25 mer sense CAGGACAAAAAGCUCCCACAGCU 322 1620 Sequence strand GC NR1H3-1555- Artificial 25 mer sense AGGACAAAAAGCUCCCACCACUG 323 1621 Sequence strand CU NR1H3-1556- Artificial 25 mer sense GGACAAAAAGCUCCCACCGAUGC 324 1622 Sequence strand UC NR1H3-1558- Artificial 25 mer sense ACAAAAAGCUCCCACCGCUACUC 325 1624 Sequence strand UC NR1H3-1559- Artificial 25 mer sense CAAAAAGCUCCCACCGCUGAUCU 326 1625 Sequence strand CU NR1H3-1560- Artificial 25 mer sense AAAAAGCUCCCACCGCUGCACUC 327 1626 Sequence strand UG NR1H3-1561- Artificial 25 mer sense AAAAGCUCCCACCGCUGCUAUCU 328 1627 Sequence strand GA NR1H3-1562- Artificial 25 mer sense AAAGCUCCCACCGCUGCUCACUG 329 1628 Sequence strand AG NR1H3-1563- Artificial 25 mer sense AAGCUCCCACCGCUGCUCUAUGA 330 1629 Sequence strand GA NR1H3-1564- Artificial 25 mer sense AGCUCCCACCGCUGCUCUCAGAG 331 1630 Sequence strand AU NR1H3-1565- Artificial 25 mer sense GCUCCCACCGCUGCUCUCUAAGA 332 1631 Sequence strand UC NR1H3-1567- Artificial 25 mer sense UCCCACCGCUGCUCUCUGAAAUC 333 1633 Sequence strand UG NR1H3-1569- Artificial 25 mer sense CCACCGCUGCUCUCUGAGAACUG 334 1635 Sequence strand GG NR1H3-1570- Artificial 25 mer sense CACCGCUGCUCUCUGAGAUAUGG 335 1636 Sequence strand GA NR1H3-1572- Artificial 25 mer sense CCGCUGCUCUCUGAGAUCUAGGA 336 1638 Sequence strand UG NR1H3-1573- Artificial 25 mer sense CGCUGCUCUCUGAGAUCUGAGAU 337 1639 Sequence strand GU NR1H3-1574- Artificial 25 mer sense GCUGCUCUCUGAGAUCUGGAAUG 338 1640 Sequence strand UG NR1H3-1577- Artificial 25 mer sense GCUCUCUGAGAUCUGGGAUAUGC 339 1643 Sequence strand AC NR1H3-1579- Artificial 25 mer sense UCUCUGAGAUCUGGGAUGUACAC 340 1645 Sequence strand GA NR1H3-1580- Artificial 25 mer sense CUCUGAGAUCUGGGAUGUGAAC 341 1646 Sequence strand GAA NR1H3-1581- Artificial 25 mer sense UCUGAGAUCUGGGAUGUGCACG 342 1647 Sequence strand AAU NR1H3-1582- Artificial 25 mer sense CUGAGAUCUGGGAUGUGCAAGA 343 1648 Sequence strand AUG NR1H3-1583- Artificial 25 mer sense UGAGAUCUGGGAUGUGCACAAA 344 1649 Sequence strand UGA NR1H3-1584- Artificial 25 mer sense GAGAUCUGGGAUGUGCACGAAU 345 1650 Sequence strand GAC NR1H3-1585- Artificial 25 mer sense AGAUCUGGGAUGUGCACGAAUG 346 1651 Sequence strand ACU NR1H3-1586- Artificial 25 mer sense GAUCUGGGAUGUGCACGAAAGA 347 1652 Sequence strand CUG NR1H3-1587- Artificial 25 mer sense AUCUGGGAUGUGCACGAAUAAC 348 1653 Sequence strand UGU NR1H3-1588- Artificial 25 mer sense UCUGGGAUGUGCACGAAUGACU 349 1654 Sequence strand GUU NR1H3-1589- Artificial 25 mer sense CUGGGAUGUGCACGAAUGAAUG 350 1655 Sequence strand UUC NR1H3-1590- Artificial 25 mer sense UGGGAUGUGCACGAAUGACAGU 351 1656 Sequence strand UCU NR1H3-1591- Artificial 25 mer sense GGGAUGUGCACGAAUGACUAUU 352 1657 Sequence strand CUG NR1H3-1592- Artificial 25 mer sense GGAUGUGCACGAAUGACUGAUC 353 1658 Sequence strand UGU NR1H3-1593- Artificial 25 mer sense GAUGUGCACGAAUGACUGUACU 354 1659 Sequence strand GUC NR1H3-1656- Artificial 25 mer sense UGGUGGCUGCCUCCUAGAAAUGG 355 1720 Sequence strand AA NR1H3-1657- Artificial 25 mer sense GGUGGCUGCCUCCUAGAAGAGGA 356 1721 Sequence strand AC NR1H3-1658- Artificial 25 mer sense GUGGCUGCCUCCUAGAAGUAGAA 357 1722 Sequence strand CA NR1H3-1659- Artificial 25 mer sense UGGCUGCCUCCUAGAAGUGAAAC 358 1723 Sequence strand AG NR1H3-1660- Artificial 25 mer sense GGCUGCCUCCUAGAAGUGGAACA 359 1724 Sequence strand GA NR1H3-1661- Artificial 25 mer sense GCUGCCUCCUAGAAGUGGAACAG 360 1725 Sequence strand AC NR1H3-1662- Artificial 25 mer sense CUGCCUCCUAGAAGUGGAAAAGA 361 1726 Sequence strand CU NR1H3-1663- Artificial 25 mer sense UGCCUCCUAGAAGUGGAACAGAC 362 1727 Sequence strand UG NR1H3-1664- Artificial 25 mer sense GCCUCCUAGAAGUGGAACAAACU 363 1728 Sequence strand GA NR1H3-1665- Artificial 25 mer sense CCUCCUAGAAGUGGAACAGACUG 364 1729 Sequence strand AG NR1H3-1666- Artificial 25 mer sense CUCCUAGAAGUGGAACAGAAUG 365 1730 Sequence strand AGA NR1H3-1667- Artificial 25 mer sense UCCUAGAAGUGGAACAGACAGA 366 1731 Sequence strand GAA NR1H3-1668- Artificial 25 mer sense CCUAGAAGUGGAACAGACUAAG 367 1732 Sequence strand AAG NR1H3-1669- Artificial 25 mer sense CUAGAAGUGGAACAGACUGAGA 368 1733 Sequence strand AGG NR1H3-1671- Artificial 25 mer sense AGAAGUGGAACAGACUGAGAAG 369 1735 Sequence strand GGC NR1H3-1677- Artificial 25 mer sense GGAACAGACUGAGAAGGGCAAA 370 1741 Sequence strand CAU NR1H3-1679- Artificial 25 mer sense AACAGACUGAGAAGGGCAAACA 371 1743 Sequence strand UUC NR1H3-1680- Artificial 25 mer sense ACAGACUGAGAAGGGCAAAAAU 372 1744 Sequence strand UCC NR1H3-1681- Artificial 25 mer sense CAGACUGAGAAGGGCAAACAUUC 373 1745 Sequence strand CU NR1H3-1682- Artificial 25 mer sense AGACUGAGAAGGGCAAACAAUCC 374 1746 Sequence strand UG NR1H3-1683- Artificial 25 mer sense GACUGAGAAGGGCAAACAUACCU 375 1747 Sequence strand GG NR1H3-1684- Artificial 25 mer sense ACUGAGAAGGGCAAACAUUACU 376 1748 Sequence strand GGG NR1H3-1685- Artificial 25 mer sense CUGAGAAGGGCAAACAUUCAUG 377 1749 Sequence strand GGA NR1H3-1686- Artificial 25 mer sense UGAGAAGGGCAAACAUUCCAGG 378 1750 Sequence strand GAG NR1H3-1687- Artificial 25 mer sense GAGAAGGGCAAACAUUCCUAGG 379 1751 Sequence strand AGC NR1H3-1728- Artificial 25 mer sense CCCGUGGCAUUAAAAGAGAAUCA 380 1792 Sequence strand AA NR1H3-1729- Artificial 25 mer sense CCGUGGCAUUAAAAGAGAGACA 381 1793 Sequence strand AAG NR1H3-1730- Artificial 25 mer sense CGUGGCAUUAAAAGAGAGUAAA 382 1794 Sequence strand AGG NR1H3-1731- Artificial 25 mer sense GUGGCAUUAAAAGAGAGUCAAA 383 1795 Sequence strand GGG NR1H3-1732- Artificial 25 mer sense UGGCAUUAAAAGAGAGUCAAAG 384 1796 Sequence strand GGU NR1H3-764- Artificial 27 mer GCGGAUCUGUUCUUCUGACAGGA 385 784-861 Sequence antisense CACA strand NR1H3-766- Artificial 27 mer AGGCGUAUCUGUUCUUCUGACAG 386 786-863 Sequence antisense GACA strand NR1H3-789- Artificial 27 mer CCUCUUGCCGCUUCAGUUUCUUC 387 809-886 Sequence antisense AGGC strand NR1H3-790- Artificial 27 mer UCCUCUUGCCGCUUCAGUUUCUU 388 810-887 Sequence antisense CAGG strand NR1H3-791- Artificial 27 mer CUCCUUUUGCCGCUUCAGUUUCU 389 811-888 Sequence antisense UCAG strand NR1H3-792- Artificial 27 mer CCUCCUCUUGCCGCUUCAGUUUC 390 812-889 Sequence antisense UUCA strand NR1H3-793- Artificial 27 mer UCCUCUUCUUGCCGCUUCAGUUU 391 813-890 Sequence antisense CUUC strand NR1H3-795- Artificial 27 mer GUUCCUCCUCUUGCCGCUUCAGU 392 815-892 Sequence antisense UUCU strand NR1H3-796- Artificial 27 mer UGUUCUUCCUCUUGCCGCUUCAG 393 816-893 Sequence antisense UUUC strand NR1H3-797- Artificial 27 mer CUGUUUCUCCUCUUGCCGCUUCA 394 817-894 Sequence antisense GUUU strand NR1H3-798- Artificial 27 mer CCUGUUCCUCCUCUUGCCGCUUC 395 818-895 Sequence antisense AGUU strand NR1H3-799- Artificial 27 mer GCCUGUUCCUCCUCUUGCCGCUU 396 819-896 Sequence antisense CAGU strand NR1H3-802- Artificial 27 mer UGAGCUUGUUCCUCCUCUUGCCG 397 822-899 Sequence antisense CUUC strand NR1H3-803- Artificial 27 mer AUGAGUCUGUUCCUCCUCUUGCC 398 823-900 Sequence antisense GCUU strand NR1H3-804- Artificial 27 mer CAUGAUCCUGUUCCUCCUCUUGC 399 824-901 Sequence antisense CGCU strand NR1H3-806- Artificial 27 mer GGCAUUAGCCUGUUCCUCCUCUU 400 826-903 Sequence antisense GCCG strand NR1H3-808- Artificial 27 mer GUGGCUUGAGCCUGUUCCUCCUC 401 828-905 Sequence antisense UUGC strand NR1H3-809- Artificial 27 mer UGUGGUAUGAGCCUGUUCCUCCU 402 829-906 Sequence antisense CUUG strand NR1H3-810- Artificial 27 mer AUGUGUCAUGAGCCUGUUCCUCC 403 830-907 Sequence antisense UCUU strand NR1H3-811- Artificial 27 mer GAUGUUGCAUGAGCCUGUUCCUC 404 831-908 Sequence antisense CUCU strand NR1H3-813- Artificial 27 mer AGGAUUUGGCAUGAGCCUGUUCC 405 833-910 Sequence antisense UCCU strand NR1H3-844 Artificial 27 mer AUUUGUGGGGGUGAGGAAGCCC 406 Sequence antisense UGGGG strand NR1H3-895- Artificial 27 mer GCGACUAGCUUCUCGAUCAUGCC 407 915-992 Sequence antisense CAGU strand NR1H3-898- Artificial 27 mer GCAGCUACGAGCUUCUCGAUCAU 408 918-995 Sequence antisense GCCC strand NR1H3-915- Artificial 27 mer GGUUAUACUGUUGCUGGGCAGC 409 935 Sequence antisense GACGA strand NR1H3-917- Artificial 27 mer CCGGUUACACUGUUGCUGGGCAG 410 937 Sequence antisense CGAC strand NR1H3-922- Artificial 27 mer GAGCGUCGGUUACACUGUUGCUG 411 942 Sequence antisense GGCA strand NR1H3-924- Artificial 27 mer AGGAGUGCCGGUUACACUGUUGC 412 944 Sequence antisense UGGG strand NR1H3-925- Artificial 27 mer AAGGAUCGCCGGUUACACUGUUG 413 945 Sequence antisense CUGG strand NR1H3-927- Artificial 27 mer AAAAGUAGCGCCGGUUACACUGU 414 947 Sequence antisense UGCU strand NR1H3-928- Artificial 27 mer GAAAAUGAGCGCCGGUUACACUG 415 948 Sequence antisense UUGC strand NR1H3-929- Artificial 27 mer AGAAAUGGAGCGCCGGUUACACU 416 949 Sequence antisense GUUG strand NR1H3-930- Artificial 27 mer CAGAAUAGGAGCGCCGGUUACAC 417 950 Sequence antisense UGUU strand NR1H3-931- Artificial 27 mer UCAGAUAAGGAGCGCCGGUUACA 418 951 Sequence antisense CUGU strand NR1H3-932- Artificial 27 mer GUCAGUAAAGGAGCGCCGGUUAC 419 952 Sequence antisense ACUG strand NR1H3-933- Artificial 27 mer GGUCAUAAAAGGAGCGCCGGUU 420 953 Sequence antisense ACACU strand NR1H3-941- Artificial 27 mer UCGAAUCCGGUCAGAAAAGGAGC 421 961 Sequence antisense GCCG strand NR1H3-944- Artificial 27 mer GACUCUAAGCCGGUCAGAAAAGG 422 964 Sequence antisense AGCG strand NR1H3-945- Artificial 27 mer UGACUUGAAGCCGGUCAGAAAA 423 965 Sequence antisense GGAGC strand NR1H3-946- Artificial 27 mer GUGACUCGAAGCCGGUCAGAAAA 424 966 Sequence antisense GGAG strand NR1H3-947- Artificial 27 mer CGUGAUUCGAAGCCGGUCAGAAA 425 967 Sequence antisense AGGA strand NR1H3-949- Artificial 27 mer GGCGUUACUCGAAGCCGGUCAGA 426 969 Sequence antisense AAAG strand NR1H3-951- Artificial 27 mer AAGGCUUGACUCGAAGCCGGUCA 427 971 Sequence antisense GAAA strand NR1H3-952- Artificial 27 mer CAAGGUGUGACUCGAAGCCGGUC 428 972 Sequence antisense AGAA strand NR1H3-953- Artificial 27 mer CCAAGUCGUGACUCGAAGCCGGU 429 973 Sequence antisense CAGA strand NR1H3-1151- Artificial 27 mer CCGAGUUGUCUCCAGAAGCAUCA 430 1171 Sequence antisense CCUG strand NR1H3-1153- Artificial 27 mer CUCCGUGAUGUCUCCAGAAGCAU 431 1173 Sequence antisense CACC strand NR1H3-1154- Artificial 27 mer CCUCCUAGAUGUCUCCAGAAGCA 432 1174 Sequence antisense UCAC strand NR1H3-1155- Artificial 27 mer ACCUCUGAGAUGUCUCCAGAAGC 433 1175 Sequence antisense AUCA strand NR1H3-1156- Artificial 27 mer UACCUUCGAGAUGUCUCCAGAAG 434 1176 Sequence antisense CAUC strand NR1H3-1157- Artificial 27 mer GUACCUCCGAGAUGUCUCCAGAA 435 1177 Sequence antisense GCAU strand NR1H3-1158- Artificial 27 mer UGUACUUCCGAGAUGUCUCCAGA 436 1178 Sequence antisense AGCA strand NR1H3-1159- Artificial 27 mer UUGUAUCUCCGAGAUGUCUCCAG 437 1179 Sequence antisense AAGC strand NR1H3-1160- Artificial 27 mer GUUGUUCCUCCGAGAUGUCUCCA 438 1180 Sequence antisense GAAG strand NR1H3-1161- Artificial 27 mer GGUUGUACCUCCGAGAUGUCUCC 439 1181 Sequence antisense AGAA strand NR1H3-1162- Artificial 27 mer GGGUUUUACCUCCGAGAUGUCUC 440 1182 Sequence antisense CAGA strand NR1H3-1163- Artificial 27 mer AGGGUUGUACCUCCGAGAUGUCU 441 1183 Sequence antisense CCAG strand NR1H3-1164- Artificial 27 mer CAGGGUUGUACCUCCGAGAUGUC 442 1184 Sequence antisense UCCA strand NR1H3-1165- Artificial 27 mer CCAGGUUUGUACCUCCGAGAUGU 443 1185 Sequence antisense CUCC strand NR1H3-1166- Artificial 27 mer CCCAGUGUUGUACCUCCGAGAUG 444 1186 Sequence antisense UCUC strand NR1H3-1167- Artificial 27 mer UCCCAUGGUUGUACCUCCGAGAU 445 1187 Sequence antisense GUCU strand NR1H3-1169- Artificial 27 mer ACUCCUAGGGUUGUACCUCCGAG 446 1189 Sequence antisense AUGU strand NR1H3-1170- Artificial 27 mer CACUCUCAGGGUUGUACCUCCGA 447 1190 Sequence antisense GAUG strand NR1H3-1171- Artificial 27 mer UCACUUCCAGGGUUGUACCUCCG 448 1191 Sequence antisense AGAU strand NR1H3-1173- Artificial 27 mer UCUCAUUCCCAGGGUUGUACCUC 449 1193 Sequence antisense CGAG strand NR1H3-1175- Artificial 27 mer ACUCUUACUCCCAGGGUUGUACC 450 1195 Sequence antisense UCCG strand NR1H3-1176- Artificial 27 mer UACUCUCACUCCCAGGGUUGUAC 451 1196 Sequence antisense CUCC strand NR1H3-1177- Artificial 27 mer AUACUUUCACUCCCAGGGUUGUA 452 1197 Sequence antisense CCUC strand NR1H3-1178- Artificial 27 mer GAUACUCUCACUCCCAGGGUUGU 453 1198 Sequence antisense ACCU strand NR1H3-1179- Artificial 27 mer UGAUAUUCUCACUCCCAGGGUUG 454 1199 Sequence antisense UACC strand NR1H3-1180- Artificial 27 mer GUGAUUCUCUCACUCCCAGGGUU 455 1200 Sequence antisense GUAC strand NR1H3-1181- Artificial 27 mer GGUGAUACUCUCACUCCCAGGGU 456 1201 Sequence antisense UGUA strand NR1H3-1182- Artificial 27 mer AGGUGUUACUCUCACUCCCAGGG 457 1202 Sequence antisense UUGU strand NR1H3-1183- Artificial 27 mer AAGGUUAUACUCUCACUCCCAGG 458 1203 Sequence antisense GUUG strand NR1H3-1184- Artificial 27 mer GAAGGUGAUACUCUCACUCCCAG 459 1204 Sequence antisense GGUU strand NR1H3-1185- Artificial 27 mer GGAAGUUGAUACUCUCACUCCCA 460 1205 Sequence antisense GGGU strand NR1H3-1186- Artificial 27 mer AGGAAUGUGAUACUCUCACUCCC 461 1206 Sequence antisense AGGG strand NR1H3-1187- Artificial 27 mer GAGGAUGGUGAUACUCUCACUCC 462 1207 Sequence antisense CAGG strand NR1H3-1188- Artificial 27 mer UGAGGUAGGUGAUACUCUCACUC 463 1208 Sequence antisense CCAG strand NR1H3-1190- Artificial 27 mer CUUGAUGAAGGUGAUACUCUCAC 464 1210 Sequence antisense UCCC strand NR1H3-1191- Artificial 27 mer CCUUGUGGAAGGUGAUACUCUCA 465 1211 Sequence antisense CUCC strand NR1H3-1192- Artificial 27 mer UCCUUUAGGAAGGUGAUACUCUC 466 1212 Sequence antisense ACUC strand NR1H3-1193- Artificial 27 mer AUCCUUGAGGAAGGUGAUACUC 467 1213 Sequence antisense UCACU strand NR1H3-1194- Artificial 27 mer AAUCCUUGAGGAAGGUGAUACU 468 1214 Sequence antisense CUCAC strand NR1H3-1196- Artificial 27 mer GAAAUUCUUGAGGAAGGUGAUA 469 1216 Sequence antisense CUCUC strand NR1H3-1197- Artificial 27 mer UGAAAUCCUUGAGGAAGGUGAU 470 1217 Sequence antisense ACUCU strand NR1H3-1198- Artificial 27 mer CUGAAUUCCUUGAGGAAGGUGA 471 1218 Sequence antisense UACUC strand NR1H3-1199- Artificial 27 mer ACUGAUAUCCUUGAGGAAGGUG 472 1219 Sequence antisense AUACU strand NR1H3-1200- Artificial 27 mer AACUGUAAUCCUUGAGGAAGGU 473 1220 Sequence antisense GAUAC strand NR1H3-1203- Artificial 27 mer UAUAAUUGAAAUCCUUGAGGAA 474 1223 Sequence antisense GGUGA strand NR1H3-1204- Artificial 27 mer UUAUAUCUGAAAUCCUUGAGGA 475 1224 Sequence antisense AGGUG strand NR1H3-1207- Artificial 27 mer CGGUUUUAACUGAAAUCCUUGA 476 1227 Sequence antisense GGAAG strand NR1H3-1211- Artificial 27 mer UUCCCUGUUAUAACUGAAAUCCU 477 1231 Sequence antisense UGAG strand NR1H3-1212- Artificial 27 mer CUUCCUGGUUAUAACUGAAAUCC 478 1232 Sequence antisense UUGA strand NR1H3-1213- Artificial 27 mer UCUUCUCGGUUAUAACUGAAAUC 479 1233 Sequence antisense CUUG strand NR1H3-1214- Artificial 27 mer GUCUUUCCGGUUAUAACUGAAA 480 1234 Sequence antisense UCCUU strand NR1H3-1215- Artificial 27 mer AGUCUUCCCGGUUAUAACUGAAA 481 1235 Sequence antisense UCCU strand NR1H3-1216- Artificial 27 mer AAGUCUUCCCGGUUAUAACUGAA 482 1236 Sequence antisense AUCC strand NR1H3-1217- Artificial 27 mer AAAGUUUUCCCGGUUAUAACUG 483 1237 Sequence antisense AAAUC strand NR1H3-1218- Artificial 27 mer CAAAGUCUUCCCGGUUAUAACUG 484 1238 Sequence antisense AAAU strand NR1H3-1219- Artificial 27 mer GCAAAUUCUUCCCGGUUAUAACU 485 1239 Sequence antisense GAAA strand NR1H3-1220- Artificial 27 mer GGCAAUGUCUUCCCGGUUAUAAC 486 1240 Sequence antisense UGAA strand NR1H3-1222- Artificial 27 mer UUGGCUAAGUCUUCCCGGUUAUA 487 1242 Sequence antisense ACUG strand NR1H3-1223- Artificial 27 mer UUUGGUAAAGUCUUCCCGGUUA 488 1243 Sequence antisense UAACU strand NR1H3-1224- Artificial 27 mer CUUUGUCAAAGUCUUCCCGGUUA 489 1244 Sequence antisense UAAC strand NR1H3-1225- Artificial 27 mer GCUUUUGCAAAGUCUUCCCGGUU 490 1245 Sequence antisense AUAA strand NR1H3-1226- Artificial 27 mer UGCUUUGGCAAAGUCUUCCCGGU 491 1246 Sequence antisense UAUA strand NR1H3-1227- Artificial 27 mer CUGCUUUGGCAAAGUCUUCCCGG 492 1247 Sequence antisense UUAU strand NR1H3-1228- Artificial 27 mer CCUGCUUUGGCAAAGUCUUCCCG 493 1248 Sequence antisense GUUA strand NR1H3-1229- Artificial 27 mer CCCUGUUUUGGCAAAGUCUUCCC 494 1249 Sequence antisense GGUU strand NR1H3-1232- Artificial 27 mer CAGCCUUGCUUUGGCAAAGUCUU 495 1252 Sequence antisense CCCG strand NR1H3-1233- Artificial 27 mer GCAGCUCUGCUUUGGCAAAGUCU 496 1253 Sequence antisense UCCC strand NR1H3-1234- Artificial 27 mer UGCAGUCCUGCUUUGGCAAAGUC 497 1254 Sequence antisense UUCC strand NR1H3-1235- Artificial 27 mer UUGCAUCCCUGCUUUGGCAAAGU 498 1255 Sequence antisense CUUC strand NR1H3-1236- Artificial 27 mer CUUGCUGCCCUGCUUUGGCAAAG 499 1256 Sequence antisense UCUU strand NR1H3-1237- Artificial 27 mer ACUUGUAGCCCUGCUUUGGCAAA 500 1257 Sequence antisense GUCU strand NR1H3-1238- Artificial 27 mer CACUUUCAGCCCUGCUUUGGCAA 501 1258 Sequence antisense AGUC strand NR1H3-1241- Artificial 27 mer UUCCAUUUGCAGCCCUGCUUUGG 502 1261 Sequence antisense CAAA strand NR1H3-1242- Artificial 27 mer AUUCCUCUUGCAGCCCUGCUUUG 503 1262 Sequence antisense GCAA strand NR1H3-1243- Artificial 27 mer AAUUCUACUUGCAGCCCUGCUUU 504 1263 Sequence antisense GGCA strand NR1H3-1244- Artificial 27 mer GAAUUUCACUUGCAGCCCUGCUU 505 1264 Sequence antisense UGGC strand NR1H3-1245- Artificial 27 mer UGAAUUCCACUUGCAGCCCUGCU 506 1265 Sequence antisense UUGG strand NR1H3-1246- Artificial 27 mer AUGAAUUCCACUUGCAGCCCUGC 507 1266 Sequence antisense UUUG strand NR1H3-1247- Artificial 27 mer GAUGAUUUCCACUUGCAGCCCUG 508 1267 Sequence antisense CUUU strand NR1H3-1248- Artificial 27 mer UGAUGUAUUCCACUUGCAGCCCU 509 1268 Sequence antisense GCUU strand NR1H3-1250- Artificial 27 mer GUUGAUGAAUUCCACUUGCAGCC 510 1270 Sequence antisense CUGC strand NR1H3-1251- Artificial 27 mer GGUUGUUGAAUUCCACUUGCAGC 511 1271 Sequence antisense CCUG strand NR1H3-1252- Artificial 27 mer GGGUUUAUGAAUUCCACUUGCA 512 1272 Sequence antisense GCCCU strand NR1H3-1253- Artificial 27 mer GGGGUUGAUGAAUUCCACUUGC 513 1273 Sequence antisense AGCCC strand NR1H3-1256- Artificial 27 mer GAUGGUGUUGAUGAAUUCCACU 514 1276 Sequence antisense UGCAG strand NR1H3-1258- Artificial 27 mer AAGAUUGGGUUGAUGAAUUCCA 515 1278 Sequence antisense CUUGC strand NR1H3-1259- Artificial 27 mer GAAGAUGGGGUUGAUGAAUUCC 516 1279 Sequence antisense ACUUG strand NR1H3-1261- Artificial 27 mer UCGAAUAUGGGGUUGAUGAAUU 517 1281 Sequence antisense CCACU strand NR1H3-1262- Artificial 27 mer CUCGAUGAUGGGGUUGAUGAAU 518 1282 Sequence antisense UCCAC strand NR1H3-1265- Artificial 27 mer GAACUUGAAGAUGGGGUUGAUG 519 1285 Sequence antisense AAUUC strand NR1H3-1266- Artificial 27 mer AGAACUCGAAGAUGGGGUUGAU 520 1286 Sequence antisense GAAUU strand NR1H3-1267- Artificial 27 mer GAGAAUUCGAAGAUGGGGUUGA 521 1287 Sequence antisense UGAAU strand NR1H3-1268- Artificial 27 mer GGAGAUCUCGAAGAUGGGGUUG 522 1288 Sequence antisense AUGAA strand NR1H3-1269- Artificial 27 mer UGGAGUACUCGAAGAUGGGGUU 523 1289 Sequence antisense GAUGA strand NR1H3-1270- Artificial 27 mer CUGGAUAACUCGAAGAUGGGGU 524 1290 Sequence antisense UGAUG strand NR1H3-1271- Artificial 27 mer CCUGGUGAACUCGAAGAUGGGG 525 1291 Sequence antisense UUGAU strand NR1H3-1272- Artificial 27 mer CCCUGUAGAACUCGAAGAUGGGG 526 1292 Sequence antisense UUGA strand NR1H3-1273- Artificial 27 mer GCCCUUGAGAACUCGAAGAUGGG 527 1293 Sequence antisense GUUG strand NR1H3-1275- Artificial 27 mer UGGCCUUGGAGAACUCGAAGAU 528 1295 Sequence antisense GGGGU strand NR1H3-1276- Artificial 27 mer AUGGCUCUGGAGAACUCGAAGA 529 1296 Sequence antisense UGGGG strand NR1H3-1277- Artificial 27 mer CAUGGUCCUGGAGAACUCGAAGA 530 1297 Sequence antisense UGGG strand NR1H3-1278- Artificial 27 mer UCAUGUCCCUGGAGAACUCGAAG 531 1298 Sequence antisense AUGG strand NR1H3-1279- Artificial 27 mer UUCAUUGCCCUGGAGAACUCGAA 532 1299 Sequence antisense GAUG strand NR1H3-1280- Artificial 27 mer AUUCAUGGCCCUGGAGAACUCGA 533 1300 Sequence antisense AGAU strand NR1H3-1281- Artificial 27 mer CAUUCUUGGCCCUGGAGAACUCG 534 1301 Sequence antisense AAGA strand NR1H3-1282- Artificial 27 mer UCAUUUAUGGCCCUGGAGAACUC 535 1302 Sequence antisense GAAG strand NR1H3-1283- Artificial 27 mer CUCAUUCAUGGCCCUGGAGAACU 536 1303 Sequence antisense CGAA strand NR1H3-1284- Artificial 27 mer GCUCAUUCAUGGCCCUGGAGAAC 537 1304 Sequence antisense UCGA strand NR1H3-1285- Artificial 27 mer AGCUCUUUCAUGGCCCUGGAGAA 538 1305 Sequence antisense CUCG strand NR1H3-1286- Artificial 27 mer CAGCUUAUUCAUGGCCCUGGAGA 539 1306 Sequence antisense ACUC strand NR1H3-1288- Artificial 27 mer UGCAGUUCAUUCAUGGCCCUGGA 540 1308 Sequence antisense GAAC strand NR1H3-1289- Artificial 27 mer UUGCAUCUCAUUCAUGGCCCUGG 541 1309 Sequence antisense AGAA strand NR1H3-1290- Artificial 27 mer GUUGCUGCUCAUUCAUGGCCCUG 542 1310 Sequence antisense GAGA strand NR1H3-1291- Artificial 27 mer AGUUGUAGCUCAUUCAUGGCCCU 543 1311 Sequence antisense GGAG strand NR1H3-1292- Artificial 27 mer GAGUUUCAGCUCAUUCAUGGCCC 544 1312 Sequence antisense UGGA strand NR1H3-1293- Artificial 27 mer UGAGUUGCAGCUCAUUCAUGGCC 545 1313 Sequence antisense CUGG strand NR1H3-1294- Artificial 27 mer UUGAGUUGCAGCUCAUUCAUGGC 546 1314 Sequence antisense CCUG strand NR1H3-1295- Artificial 27 mer AUUGAUUUGCAGCUCAUUCAUG 547 1315 Sequence antisense GCCCU strand NR1H3-1296- Artificial 27 mer CAUUGUGUUGCAGCUCAUUCAUG 548 1316 Sequence antisense GCCC strand NR1H3-1297- Artificial 27 mer UCAUUUAGUUGCAGCUCAUUCAU 549 1317 Sequence antisense GGCC strand NR1H3-1338- Artificial 27 mer CAGAGUAGAUGCUGAUAGCAAU 550 1358 Sequence antisense GAGCA strand NR1H3-1339- Artificial 27 mer GCAGAUAAGAUGCUGAUAGCAA 551 1359 Sequence antisense UGAGC strand NR1H3-1340- Artificial 27 mer UGCAGUGAAGAUGCUGAUAGCA 552 1360 Sequence antisense AUGAG strand NR1H3-1341- Artificial 27 mer CUGCAUAGAAGAUGCUGAUAGC 553 1361 Sequence antisense AAUGA strand NR1H3-1342- Artificial 27 mer UCUGCUGAGAAGAUGCUGAUAG 554 1362 Sequence antisense CAAUG strand NR1H3-1343- Artificial 27 mer GUCUGUAGAGAAGAUGCUGAUA 555 1363 Sequence antisense GCAAU strand NR1H3-1344- Artificial 27 mer GGUCUUCAGAGAAGAUGCUGAU 556 1364 Sequence antisense AGCAA strand NR1H3-1345- Artificial 27 mer CGGUCUGCAGAGAAGAUGCUGA 557 1365 Sequence antisense UAGCA strand NR1H3-1346- Artificial 27 mer CCGGUUUGCAGAGAAGAUGCUG 558 1366 Sequence antisense AUAGC strand NR1H3-1347- Artificial 27 mer GCCGGUCUGCAGAGAAGAUGCUG 559 1367 Sequence antisense AUAG strand NR1H3-1377- Artificial 27 mer UCUCUUCCUGGAGCUGGUCCUGC 560 1443 Sequence antisense ACGU strand NR1H3-1379- Artificial 27 mer CCUCUUUACCUGGAGCUGGUCCU 561 1445 Sequence antisense GCAC strand NR1H3-1383- Artificial 27 mer GCAGCUUCUCUACCUGGAGCUGG 562 1449 Sequence antisense UCCU strand NR1H3-1384- Artificial 27 mer UGCAGUCUCUCUACCUGGAGCUG 563 1450 Sequence antisense GUCC strand NR1H3-1385- Artificial 27 mer CUGCAUCCUCUCUACCUGGAGCU 564 1451 Sequence antisense GGUC strand NR1H3-1387- Artificial 27 mer UGCUGUAGCCUCUCUACCUGGAG 565 1453 Sequence antisense CUGG strand NR1H3-1388- Artificial 27 mer GUGCUUCAGCCUCUCUACCUGGA 566 1454 Sequence antisense GCUG strand NR1H3-1391- Artificial 27 mer UGUGUUCUGCAGCCUCUCUACCU 567 1457 Sequence antisense GGAG strand NR1H3-1393- Artificial 27 mer UAUGUUUGCUGCAGCCUCUCUAC 568 1459 Sequence antisense CUGG strand NR1H3-1394- Artificial 27 mer AUAUGUGUGCUGCAGCCUCUCUA 569 1460 Sequence antisense CCUG strand NR1H3-1395- Artificial 27 mer CAUAUUUGUGCUGCAGCCUCUCU 570 1461 Sequence antisense ACCU strand NR1H3-1396- Artificial 27 mer ACAUAUGUGUGCUGCAGCCUCUC 571 1462 Sequence antisense UACC strand NR1H3-1397- Artificial 27 mer CACAUUUGUGUGCUGCAGCCUCU 572 1463 Sequence antisense CUAC strand NR1H3-1398- Artificial 27 mer CCACAUAUGUGUGCUGCAGCCUC 573 1464 Sequence antisense UCUA strand NR1H3-1399- Artificial 27 mer UCCACUUAUGUGUGCUGCAGCCU 574 1465 Sequence antisense CUCU strand NR1H3-1400- Artificial 27 mer UUCCAUAUAUGUGUGCUGCAGCC 575 1466 Sequence antisense UCUC strand NR1H3-1401- Artificial 27 mer CUUCCUCAUAUGUGUGCUGCAGC 576 1467 Sequence antisense CUCU strand NR1H3-1402- Artificial 27 mer GCUUCUACAUAUGUGUGCUGCAG 577 1468 Sequence antisense CCUC strand NR1H3-1403- Artificial 27 mer GGCUUUCACAUAUGUGUGCUGCA 578 1469 Sequence antisense GCCU strand NR1H3-1404- Artificial 27 mer GGGCUUCCACAUAUGUGUGCUGC 579 1470 Sequence antisense AGCC strand NR1H3-1406- Artificial 27 mer CAGGGUUUCCACAUAUGUGUGCU 580 1472 Sequence antisense GCAG strand NR1H3-1407- Artificial 27 mer GCAGGUCUUCCACAUAUGUGUGC 581 1473 Sequence antisense UGCA strand NR1H3-1408- Artificial 27 mer UGCAGUGCUUCCACAUAUGUGUG 582 1474 Sequence antisense CUGC strand NR1H3-1410- Artificial 27 mer CAUGCUGGGCUUCCACAUAUGUG 583 1476 Sequence antisense UGCU strand NR1H3-1411- Artificial 27 mer GCAUGUAGGGCUUCCACAUAUGU 584 1477 Sequence antisense GUGC strand NR1H3-1412- Artificial 27 mer GGCAUUCAGGGCUUCCACAUAUG 585 1478 Sequence antisense UGUG strand NR1H3-1413- Artificial 27 mer AGGCAUGCAGGGCUUCCACAUAU 586 1479 Sequence antisense GUGU strand NR1H3-1414- Artificial 27 mer UAGGCUUGCAGGGCUUCCACAUA 587 1480 Sequence antisense UGUG strand NR1H3-1415- Artificial 27 mer GUAGGUAUGCAGGGCUUCCACAU 588 1481 Sequence antisense AUGU strand NR1H3-1416- Artificial 27 mer CGUAGUCAUGCAGGGCUUCCACA 589 1482 Sequence antisense UAUG strand NR1H3-1417- Artificial 27 mer ACGUAUGCAUGCAGGGCUUCCAC 590 1483 Sequence antisense AUAU strand NR1H3-1418- Artificial 27 mer GACGUUGGCAUGCAGGGCUUCCA 591 1484 Sequence antisense CAUA strand NR1H3-1419- Artificial 27 mer AGACGUAGGCAUGCAGGGCUUCC 592 1485 Sequence antisense ACAU strand NR1H3-1420- Artificial 27 mer GAGACUUAGGCAUGCAGGGCUUC 593 1486 Sequence antisense CACA strand NR1H3-1421- Artificial 27 mer GGAGAUGUAGGCAUGCAGGGCU 594 1487 Sequence antisense UCCAC strand NR1H3-1422- Artificial 27 mer UGGAGUCGUAGGCAUGCAGGGC 595 1488 Sequence antisense UUCCA strand NR1H3-1423- Artificial 27 mer AUGGAUACGUAGGCAUGCAGGG 596 1489 Sequence antisense CUUCC strand NR1H3-1424- Artificial 27 mer GAUGGUGACGUAGGCAUGCAGG 597 1490 Sequence antisense GCUUC strand NR1H3-1425- Artificial 27 mer GGAUGUAGACGUAGGCAUGCAG 598 1491 Sequence antisense GGCUU strand NR1H3-1426- Artificial 27 mer UGGAUUGAGACGUAGGCAUGCA 599 1492 Sequence antisense GGGCU strand NR1H3-1427- Artificial 27 mer GUGGAUGGAGACGUAGGCAUGC 600 1493 Sequence antisense AGGGC strand NR1H3-1428- Artificial 27 mer GGUGGUUGGAGACGUAGGCAUG 601 1494 Sequence antisense CAGGG strand NR1H3-1429- Artificial 27 mer UGGUGUAUGGAGACGUAGGCAU 602 1495 Sequence antisense GCAGG strand NR1H3-1430- Artificial 27 mer AUGGUUGAUGGAGACGUAGGCA 603 1496 Sequence antisense UGCAG strand NR1H3-1431- Artificial 27 mer GAUGGUGGAUGGAGACGUAGGC 604 1497 Sequence antisense AUGCA strand NR1H3-1432- Artificial 27 mer GGAUGUUGGAUGGAGACGUAGG 605 1498 Sequence antisense CAUGC strand NR1H3-1433- Artificial 27 mer GGGAUUGUGGAUGGAGACGUAG 606 1499 Sequence antisense GCAUG strand NR1H3-1434- Artificial 27 mer GGGGAUGGUGGAUGGAGACGUA 607 1500 Sequence antisense GGCAU strand NR1H3-1435- Artificial 27 mer UGGGGUUGGUGGAUGGAGACGU 608 1501 Sequence antisense AGGCA strand NR1H3-1436- Artificial 27 mer AUGGGUAUGGUGGAUGGAGACG 609 1502 Sequence antisense UAGGC strand NR1H3-1437- Artificial 27 mer CAUGGUGAUGGUGGAUGGAGAC 610 1503 Sequence antisense GUAGG strand NR1H3-1438- Artificial 27 mer UCAUGUGGAUGGUGGAUGGAGA 611 1504 Sequence antisense CGUAG strand NR1H3-1439- Artificial 27 mer GUCAUUGGGAUGGUGGAUGGAG 612 1505 Sequence antisense ACGUA strand NR1H3-1440- Artificial 27 mer GGUCAUGGGGAUGGUGGAUGGA 613 1506 Sequence antisense GACGU strand NR1H3-1442- Artificial 27 mer UCGGUUAUGGGGAUGGUGGAUG 614 1508 Sequence antisense GAGAC strand NR1H3-1443- Artificial 27 mer GUCGGUCAUGGGGAUGGUGGAU 615 1509 Sequence antisense GGAGA strand NR1H3-1444- Artificial 27 mer AGUCGUUCAUGGGGAUGGUGGA 616 1510 Sequence antisense UGGAG strand NR1H3-1445- Artificial 27 mer CAGUCUGUCAUGGGGAUGGUGG 617 1511 Sequence antisense AUGGA strand NR1H3-1446- Artificial 27 mer UCAGUUGGUCAUGGGGAUGGUG 618 1512 Sequence antisense GAUGG strand NR1H3-1447- Artificial 27 mer AUCAGUCGGUCAUGGGGAUGGU 619 1513 Sequence antisense GGAUG strand NR1H3-1448- Artificial 27 mer CAUCAUUCGGUCAUGGGGAUGG 620 1514 Sequence antisense UGGAU strand NR1H3-1449- Artificial 27 mer ACAUCUGUCGGUCAUGGGGAUG 621 1515 Sequence antisense GUGGA strand NR1H3-1450- Artificial 27 mer AACAUUAGUCGGUCAUGGGGAU 622 1516 Sequence antisense GGUGG strand NR1H3-1451- Artificial 27 mer GAACAUCAGUCGGUCAUGGGGA 623 1517 Sequence antisense UGGUG strand NR1H3-1452- Artificial 27 mer GGAACUUCAGUCGGUCAUGGGG 624 1518 Sequence antisense AUGGU strand NR1H3-1453- Artificial 27 mer GGGAAUAUCAGUCGGUCAUGGG 625 1519 Sequence antisense GAUGG strand NR1H3-1454- Artificial 27 mer UGGGAUCAUCAGUCGGUCAUGG 626 1520 Sequence antisense GGAUG strand NR1H3-1455- Artificial 27 mer GUGGGUACAUCAGUCGGUCAUG 627 1521 Sequence antisense GGGAU strand NR1H3-1456- Artificial 27 mer CGUGGUAACAUCAGUCGGUCAUG 628 1522 Sequence antisense GGGA strand NR1H3-1457- Artificial 27 mer CCGUGUGAACAUCAGUCGGUCAU 629 1523 Sequence antisense GGGG strand NR1H3-1459- Artificial 27 mer AUCCGUGGGAACAUCAGUCGGUC 630 1525 Sequence antisense AUGG strand NR1H3-1460- Artificial 27 mer CAUCCUUGGGAACAUCAGUCGGU 631 1526 Sequence antisense CAUG strand NR1H3-1461- Artificial 27 mer GCAUCUGUGGGAACAUCAGUCGG 632 1527 Sequence antisense UCAU strand NR1H3-1462- Artificial 27 mer AGCAUUCGUGGGAACAUCAGUCG 633 1528 Sequence antisense GUCA strand NR1H3-1463- Artificial 27 mer UAGCAUCCGUGGGAACAUCAGUC 634 1529 Sequence antisense GGUC strand NR1H3-1465- Artificial 27 mer AUUAGUAUCCGUGGGAACAUCA 635 1531 Sequence antisense GUCGG strand NR1H3-1466- Artificial 27 mer CAUUAUCAUCCGUGGGAACAUCA 636 1532 Sequence antisense GUCG strand NR1H3-1468- Artificial 27 mer UUCAUUAGCAUCCGUGGGAACAU 637 1534 Sequence antisense CAGU strand NR1H3-1469- Artificial 27 mer UUUCAUUAGCAUCCGUGGGAACA 638 1535 Sequence antisense UCAG strand NR1H3-1471- Artificial 27 mer AGUUUUAUUAGCAUCCGUGGGA 639 1537 Sequence antisense ACAUC strand NR1H3-1472- Artificial 27 mer CAGUUUCAUUAGCAUCCGUGGGA 640 1538 Sequence antisense ACAU strand NR1H3-1473- Artificial 27 mer CCAGUUUCAUUAGCAUCCGUGGG 641 1539 Sequence antisense AACA strand NR1H3-1474- Artificial 27 mer ACCAGUUUCAUUAGCAUCCGUGG 642 1540 Sequence antisense GAAC strand NR1H3-1475- Artificial 27 mer CACCAUUUUCAUUAGCAUCCGUG 643 1541 Sequence antisense GGAA strand NR1H3-1476- Artificial 27 mer UCACCUGUUUCAUUAGCAUCCGU 644 1542 Sequence antisense GGGA strand NR1H3-1477- Artificial 27 mer CUCACUAGUUUCAUUAGCAUCCG 645 1543 Sequence antisense UGGG strand NR1H3-1478- Artificial 27 mer GCUCAUCAGUUUCAUUAGCAUCC 646 1544 Sequence antisense GUGG strand NR1H3-1479- Artificial 27 mer GGCUCUCCAGUUUCAUUAGCAUC 647 1545 Sequence antisense CGUG strand NR1H3-1480- Artificial 27 mer AGGCUUACCAGUUUCAUUAGCAU 648 1546 Sequence antisense CCGU strand NR1H3-1481- Artificial 27 mer GAGGCUCACCAGUUUCAUUAGCA 649 1547 Sequence antisense UCCG strand NR1H3-1483- Artificial 27 mer CGGAGUCUCACCAGUUUCAUUAG 650 1549 Sequence antisense CAUC strand NR1H3-1484- Artificial 27 mer CCGGAUGCUCACCAGUUUCAUUA 651 1550 Sequence antisense GCAU strand NR1H3-1485- Artificial 27 mer UCCGGUGGCUCACCAGUUUCAUU 652 1551 Sequence antisense AGCA strand NR1H3-1486- Artificial 27 mer GUCCGUAGGCUCACCAGUUUCAU 653 1552 Sequence antisense UAGC strand NR1H3-1487- Artificial 27 mer GGUCCUGAGGCUCACCAGUUUCA 654 1553 Sequence antisense UUAG strand NR1H3-1488- Artificial 27 mer GGGUCUGGAGGCUCACCAGUUUC 655 1554 Sequence antisense AUUA strand NR1H3-1489- Artificial 27 mer AGGGUUCGGAGGCUCACCAGUUU 656 1555 Sequence antisense CAUU strand NR1H3-1491- Artificial 27 mer UCAGGUUCCGGAGGCUCACCAGU 657 1557 Sequence antisense UUCA strand NR1H3-1492- Artificial 27 mer CUCAGUGUCCGGAGGCUCACCAG 658 1558 Sequence antisense UUUC strand NR1H3-1494- Artificial 27 mer UGCUCUGGGUCCGGAGGCUCACC 659 1560 Sequence antisense AGUU strand NR1H3-1505- Artificial 27 mer UGAGUUGACGCUGCUCAGGGUCC 660 1571 Sequence antisense GGAG strand NR1H3-1507- Artificial 27 mer UCUGAUUGGACGCUGCUCAGGGU 661 1573 Sequence antisense CCGG strand NR1H3-1508- Artificial 27 mer CUCUGUGUGGACGCUGCUCAGGG 662 1574 Sequence antisense UCCG strand NR1H3-1509- Artificial 27 mer GCUCUUAGUGGACGCUGCUCAGG 663 1575 Sequence antisense GUCC strand NR1H3-1510- Artificial 27 mer UGCUCUGAGUGGACGCUGCUCAG 664 1576 Sequence antisense GGUC strand NR1H3-1511- Artificial 27 mer UUGCUUUGAGUGGACGCUGCUCA 665 1577 Sequence antisense GGGU strand NR1H3-1512- Artificial 27 mer CUUGCUCUGAGUGGACGCUGCUC 666 1578 Sequence antisense AGGG strand NR1H3-1513- Artificial 27 mer ACUUGUUCUGAGUGGACGCUGCU 667 1579 Sequence antisense CAGG strand NR1H3-1514- Artificial 27 mer CACUUUCUCUGAGUGGACGCUGC 668 1580 Sequence antisense UCAG strand NR1H3-1515- Artificial 27 mer ACACUUGCUCUGAGUGGACGCUG 669 1581 Sequence antisense CUCA strand NR1H3-1516- Artificial 27 mer AACACUUGCUCUGAGUGGACGCU 670 1582 Sequence antisense GCUC strand NR1H3-1517- Artificial 27 mer AAACAUUUGCUCUGAGUGGACGC 671 1583 Sequence antisense UGCU strand NR1H3-1518- Artificial 27 mer CAAACUCUUGCUCUGAGUGGACG 672 1584 Sequence antisense CUGC strand NR1H3-1519- Artificial 27 mer GCAAAUACUUGCUCUGAGUGGAC 673 1585 Sequence antisense GCUG strand NR1H3-1520- Artificial 27 mer UGCAAUCACUUGCUCUGAGUGGA 674 1586 Sequence antisense CGCU strand NR1H3-1521- Artificial 27 mer GUGCAUACACUUGCUCUGAGUGG 675 1587 Sequence antisense ACGC strand NR1H3-1522- Artificial 27 mer AGUGCUAACACUUGCUCUGAGUG 676 1588 Sequence antisense GACG strand NR1H3-1523- Artificial 27 mer CAGUGUAAACACUUGCUCUGAGU 677 1589 Sequence antisense GGAC strand NR1H3-1525- Artificial 27 mer CGCAGUGCAAACACUUGCUCUGA 678 1591 Sequence antisense GUGG strand NR1H3-1526- Artificial 27 mer ACGCAUUGCAAACACUUGCUCUG 679 1592 Sequence antisense AGUG strand NR1H3-1527- Artificial 27 mer GACGCUGUGCAAACACUUGCUCU 680 1593 Sequence antisense GAGU strand NR1H3-1528- Artificial 27 mer AGACGUAGUGCAAACACUUGCUC 681 1594 Sequence antisense UGAG strand NR1H3-1529- Artificial 27 mer CAGACUCAGUGCAAACACUUGCU 682 1595 Sequence antisense CUGA strand NR1H3-1530- Artificial 27 mer GCAGAUGCAGUGCAAACACUUGC 683 1596 Sequence antisense UCUG strand NR1H3-1531- Artificial 27 mer UGCAGUCGCAGUGCAAACACUUG 684 1597 Sequence antisense CUCU strand NR1H3-1532- Artificial 27 mer CUGCAUACGCAGUGCAAACACUU 685 1598 Sequence antisense GCUC strand NR1H3-1533- Artificial 27 mer CCUGCUGACGCAGUGCAAACACU 686 1599 Sequence antisense UGCU strand NR1H3-1534- Artificial 27 mer UCCUGUAGACGCAGUGCAAACAC 687 1600 Sequence antisense UUGC strand NR1H3-1535- Artificial 27 mer GUCCUUCAGACGCAGUGCAAACA 688 1601 Sequence antisense CUUG strand NR1H3-1536- Artificial 27 mer UGUCCUGCAGACGCAGUGCAAAC 689 1602 Sequence antisense ACUU strand NR1H3-1537- Artificial 27 mer UUGUCUUGCAGACGCAGUGCAAA 690 1603 Sequence antisense CACU strand NR1H3-1538- Artificial 27 mer UUUGUUCUGCAGACGCAGUGCAA 691 1604 Sequence antisense ACAC strand NR1H3-1539- Artificial 27 mer UUUUGUCCUGCAGACGCAGUGCA 692 1605 Sequence antisense AACA strand NR1H3-1540- Artificial 27 mer UUUUUUUCCUGCAGACGCAGUGC 693 1606 Sequence antisense AAAC strand NR1H3-1541- Artificial 27 mer CUUUUUGUCCUGCAGACGCAGUG 694 1607 Sequence antisense CAAA strand NR1H3-1542- Artificial 27 mer GCUUUUUGUCCUGCAGACGCAGU 695 1608 Sequence antisense GCAA strand NR1H3-1543- Artificial 27 mer AGCUUUUUGUCCUGCAGACGCAG 696 1609 Sequence antisense UGCA strand NR1H3-1544- Artificial 27 mer GAGCUUUUUGUCCUGCAGACGCA 697 1610 Sequence antisense GUGC strand NR1H3-1545- Artificial 27 mer GGAGCUUUUUGUCCUGCAGACGC 698 1611 Sequence antisense AGUG strand NR1H3-1546- Artificial 27 mer GGGAGUUUUUUGUCCUGCAGAC 699 1612 Sequence antisense GCAGU strand NR1H3-1547- Artificial 27 mer UGGGAUCUUUUUGUCCUGCAGAC 700 1613 Sequence antisense GCAG strand NR1H3-1548- Artificial 27 mer GUGGGUGCUUUUUGUCCUGCAG 701 1614 Sequence antisense ACGCA strand NR1H3-1549- Artificial 27 mer GGUGGUAGCUUUUUGUCCUGCA 702 1615 Sequence antisense GACGC strand NR1H3-1550- Artificial 27 mer CGGUGUGAGCUUUUUGUCCUGCA 703 1616 Sequence antisense GACG strand NR1H3-1551- Artificial 27 mer GCGGUUGGAGCUUUUUGUCCUGC 704 1617 Sequence antisense AGAC strand NR1H3-1553- Artificial 27 mer CAGCGUUGGGAGCUUUUUGUCCU 705 1619 Sequence antisense GCAG strand NR1H3-1554- Artificial 27 mer GCAGCUGUGGGAGCUUUUUGUCC 706 1620 Sequence antisense UGCA strand NR1H3-1555- Artificial 27 mer AGCAGUGGUGGGAGCUUUUUGU 707 1621 Sequence antisense CCUGC strand NR1H3-1556- Artificial 27 mer GAGCAUCGGUGGGAGCUUUUUG 708 1622 Sequence antisense UCCUG strand NR1H3-1558- Artificial 27 mer GAGAGUAGCGGUGGGAGCUUUU 709 1624 Sequence antisense UGUCC strand NR1H3-1559- Artificial 27 mer AGAGAUCAGCGGUGGGAGCUUU 710 1625 Sequence antisense UUGUC strand NR1H3-1560- Artificial 27 mer CAGAGUGCAGCGGUGGGAGCUU 711 1626 Sequence antisense UUUGU strand NR1H3-1561- Artificial 27 mer UCAGAUAGCAGCGGUGGGAGCU 712 1627 Sequence antisense UUUUG strand NR1H3-1562- Artificial 27 mer CUCAGUGAGCAGCGGUGGGAGCU 713 1628 Sequence antisense UUUU strand NR1H3-1563- Artificial 27 mer UCUCAUAGAGCAGCGGUGGGAGC 714 1629 Sequence antisense UUUU strand NR1H3-1564- Artificial 27 mer AUCUCUGAGAGCAGCGGUGGGA 715 1630 Sequence antisense GCUUU strand NR1H3-1565- Artificial 27 mer GAUCUUAGAGAGCAGCGGUGGG 716 1631 Sequence antisense AGCUU strand NR1H3-1567- Artificial 27 mer CAGAUUUCAGAGAGCAGCGGUG 717 1633 Sequence antisense GGAGC strand NR1H3-1569- Artificial 27 mer CCCAGUUCUCAGAGAGCAGCGGU 718 1635 Sequence antisense GGGA strand NR1H3-1570- Artificial 27 mer UCCCAUAUCUCAGAGAGCAGCGG 719 1636 Sequence antisense UGGG strand NR1H3-1572- Artificial 27 mer CAUCCUAGAUCUCAGAGAGCAGC 720 1638 Sequence antisense GGUG strand NR1H3-1573- Artificial 27 mer ACAUCUCAGAUCUCAGAGAGCAG 721 1639 Sequence antisense CGGU strand NR1H3-1574- Artificial 27 mer CACAUUCCAGAUCUCAGAGAGCA 722 1640 Sequence antisense GCGG strand NR1H3-1577- Artificial 27 mer GUGCAUAUCCCAGAUCUCAGAGA 723 1643 Sequence antisense GCAG strand NR1H3-1579- Artificial 27 mer UCGUGUACAUCCCAGAUCUCAGA 724 1645 Sequence antisense GAGC strand NR1H3-1580- Artificial 27 mer UUCGUUCACAUCCCAGAUCUCAG 725 1646 Sequence antisense AGAG strand NR1H3-1581- Artificial 27 mer AUUCGUGCACAUCCCAGAUCUCA 726 1647 Sequence antisense GAGA strand NR1H3-1582- Artificial 27 mer CAUUCUUGCACAUCCCAGAUCUC 727 1648 Sequence antisense AGAG strand NR1H3-1583- Artificial 27 mer UCAUUUGUGCACAUCCCAGAUCU 728 1649 Sequence antisense CAGA strand NR1H3-1584- Artificial 27 mer GUCAUUCGUGCACAUCCCAGAUC 729 1650 Sequence antisense UCAG strand NR1H3-1585- Artificial 27 mer AGUCAUUCGUGCACAUCCCAGAU 730 1651 Sequence antisense CUCA strand NR1H3-1586- Artificial 27 mer CAGUCUUUCGUGCACAUCCCAGA 731 1652 Sequence antisense UCUC strand NR1H3-1587- Artificial 27 mer ACAGUUAUUCGUGCACAUCCCAG 732 1653 Sequence antisense AUCU strand NR1H3-1588- Artificial 27 mer AACAGUCAUUCGUGCACAUCCCA 733 1654 Sequence antisense GAUC strand NR1H3-1589- Artificial 27 mer GAACAUUCAUUCGUGCACAUCCC 734 1655 Sequence antisense AGAU strand NR1H3-1590- Artificial 27 mer AGAACUGUCAUUCGUGCACAUCC 735 1656 Sequence antisense CAGA strand NR1H3-1591- Artificial 27 mer CAGAAUAGUCAUUCGUGCACAUC 736 1657 Sequence antisense CCAG strand NR1H3-1592- Artificial 27 mer ACAGAUCAGUCAUUCGUGCACAU 737 1658 Sequence antisense CCCA strand NR1H3-1593- Artificial 27 mer GACAGUACAGUCAUUCGUGCACA 738 1659 Sequence antisense UCCC strand NR1H3-1656- Artificial 27 mer UUCCAUUUCUAGGAGGCAGCCAC 739 1720 Sequence antisense CAGG strand NR1H3-1657- Artificial 27 mer GUUCCUCUUCUAGGAGGCAGCCA 740 1721 Sequence antisense CCAG strand NR1H3-1658- Artificial 27 mer UGUUCUACUUCUAGGAGGCAGCC 741 1722 Sequence antisense ACCA strand NR1H3-1659- Artificial 27 mer CUGUUUCACUUCUAGGAGGCAGC 742 1723 Sequence antisense CACC strand NR1H3-1660- Artificial 27 mer UCUGUUCCACUUCUAGGAGGCAG 743 1724 Sequence antisense CCAC strand NR1H3-1661- Artificial 27 mer GUCUGUUCCACUUCUAGGAGGCA 744 1725 Sequence antisense GCCA strand NR1H3-1662- Artificial 27 mer AGUCUUUUCCACUUCUAGGAGGC 745 1726 Sequence antisense AGCC strand NR1H3-1663- Artificial 27 mer CAGUCUGUUCCACUUCUAGGAGG 746 1727 Sequence antisense CAGC strand NR1H3-1664- Artificial 27 mer UCAGUUUGUUCCACUUCUAGGAG 747 1728 Sequence antisense GCAG strand NR1H3-1665- Artificial 27 mer CUCAGUCUGUUCCACUUCUAGGA 748 1729 Sequence antisense GGCA strand NR1H3-1666- Artificial 27 mer UCUCAUUCUGUUCCACUUCUAGG 749 1730 Sequence antisense AGGC strand NR1H3-1667- Artificial 27 mer UUCUCUGUCUGUUCCACUUCUAG 750 1731 Sequence antisense GAGG strand NR1H3-1668- Artificial 27 mer CUUCUUAGUCUGUUCCACUUCUA 751 1732 Sequence antisense GGAG strand NR1H3-1669- Artificial 27 mer CCUUCUCAGUCUGUUCCACUUCU 752 1733 Sequence antisense AGGA strand NR1H3-1671- Artificial 27 mer GCCCUUCUCAGUCUGUUCCACUU 753 1735 Sequence antisense CUAG strand NR1H3-1677- Artificial 27 mer AUGUUUGCCCUUCUCAGUCUGUU 754 1741 Sequence antisense CCAC strand NR1H3-1679- Artificial 27 mer GAAUGUUUGCCCUUCUCAGUCUG 755 1743 Sequence antisense UUCC strand NR1H3-1680- Artificial 27 mer GGAAUUUUUGCCCUUCUCAGUCU 756 1744 Sequence antisense GUUC strand NR1H3-1681- Artificial 27 mer AGGAAUGUUUGCCCUUCUCAGUC 757 1745 Sequence antisense UGUU strand NR1H3-1682- Artificial 27 mer CAGGAUUGUUUGCCCUUCUCAGU 758 1746 Sequence antisense CUGU strand NR1H3-1683- Artificial 27 mer CCAGGUAUGUUUGCCCUUCUCAG 759 1747 Sequence antisense UCUG strand NR1H3-1684- Artificial 27 mer CCCAGUAAUGUUUGCCCUUCUCA 760 1748 Sequence antisense GUCU strand NR1H3-1685- Artificial 27 mer UCCCAUGAAUGUUUGCCCUUCUC 761 1749 Sequence antisense AGUC strand NR1H3-1686- Artificial 27 mer CUCCCUGGAAUGUUUGCCCUUCU 762 1750 Sequence antisense CAGU strand NR1H3-1687- Artificial 27 mer GCUCCUAGGAAUGUUUGCCCUUC 763 1751 Sequence antisense UCAG strand NR1H3-1728- Artificial 27 mer UUUGAUUCUCUUUUAAUGCCACG 764 1792 Sequence antisense GGAG strand NR1H3-1729- Artificial 27 mer CUUUGUCUCUCUUUUAAUGCCAC 765 1793 Sequence antisense GGGA strand NR1H3-1730- Artificial 27 mer CCUUUUACUCUCUUUUAAUGCCA 766 1794 Sequence antisense CGGG strand NR1H3-1731- Artificial 27 mer CCCUUUGACUCUCUUUUAAUGCC 767 1795 Sequence antisense ACGG strand NR1H3-1732- Artificial 27 mer ACCCUUUGACUCUCUUUUAAUGC 768 1796 Sequence antisense CACG strand NR1H3-763- Artificial 36 mer sense GUGUCCUGUCAGAAGAACAAGCA 769 783-860 Sequence strand GCCGAAAGGCUGC NR1H3-765- Artificial 36 mer sense GUCCUGUCAGAAGAACAGAAGCA 770 785-862 Sequence strand GCCGAAAGGCUGC NR1H3-767- Artificial 36 mer sense CCUGUCAGAAGAACAGAUCAGCA 771 787-864 Sequence strand GCCGAAAGGCUGC NR1H3-768- Artificial 36 mer sense CUGUCAGAAGAACAGAUCCAGCA 772 788-865 Sequence strand GCCGAAAGGCUGC NR1H3-769- Artificial 36 mer sense UGUCAGAAGAACAGAUCCGAGCA 773 789-866 Sequence strand GCCGAAAGGCUGC NR1H3-794- Artificial 36 mer sense GAAACUGAAGCGGCAAGAGAGC 774 814-891 Sequence strand AGCCGAAAGGCUGC NR1H3-1152- Artificial 36 mer sense GUGAUGCUUCUGGAGACAUAGC 775 1172-1249 Sequence strand AGCCGAAAGGCUGC NR1H3-1189- Artificial 36 mer sense GGAGUGAGAGUAUCACCUUAGC 776 1209-1286 Sequence strand AGCCGAAAGGCUGC NR1H3-1195- Artificial 36 mer sense AGAGUAUCACCUUCCUCAAAGCA 777 1215-1292 Sequence strand GCCGAAAGGCUGC NR1H3-1200- Artificial 36 mer sense AUCACCUUCCUCAAGGAUUAGCA 778 1220-1297 Sequence strand GCCGAAAGGCUGC NR1H3-1201- Artificial 36 mer sense UCACCUUCCUCAAGGAUUUAGCA 779 1221-1298 Sequence strand GCCGAAAGGCUGC NR1H3-1202- Artificial 36 mer sense CACCUUCCUCAAGGAUUUCAGCA 780 1222-1299 Sequence strand GCCGAAAGGCUGC NR1H3-1203- Artificial 36 mer sense ACCUUCCUCAAGGAUUUCAAGCA 781 1223-1300 Sequence strand GCCGAAAGGCUGC NR1H3-1204- Artificial 36 mer sense CCUUCCUCAAGGAUUUCAGAGCA 782 1224-1301 Sequence strand GCCGAAAGGCUGC NR1H3-1205- Artificial 36 mer sense CUUCCUCAAGGAUUUCAGUAGCA 783 1225-1302 Sequence strand GCCGAAAGGCUGC NR1H3-1206- Artificial 36 mer sense UUCCUCAAGGAUUUCAGUUAGCA 784 1226-1303 Sequence strand GCCGAAAGGCUGC NR1H3-1208- Artificial 36 mer sense CCUCAAGGAUUUCAGUUAUAGCA 785 1228-1305 Sequence strand GCCGAAAGGCUGC NR1H3-1209- Artificial 36 mer sense CUCAAGGAUUUCAGUUAUAAGC 786 1229-1306 Sequence strand AGCCGAAAGGCUGC NR1H3-1210- Artificial 36 mer sense UCAAGGAUUUCAGUUAUAAAGC 787 1230-1307 Sequence strand AGCCGAAAGGCUGC NR1H3-1211- Artificial 36 mer sense CAAGGAUUUCAGUUAUAACAGC 788 1231-1308 Sequence strand AGCCGAAAGGCUGC NR1H3-1212- Artificial 36 mer sense AAGGAUUUCAGUUAUAACCAGC 789 1232-1309 Sequence strand AGCCGAAAGGCUGC NR1H3-1213- Artificial 36 mer sense AGGAUUUCAGUUAUAACCGAGC 790 1233-1310 Sequence strand AGCCGAAAGGCUGC NR1H3-1214- Artificial 36 mer sense GGAUUUCAGUUAUAACCGGAGC 791 1234-1311 Sequence strand AGCCGAAAGGCUGC NR1H3-1221- Artificial 36 mer sense AGUUAUAACCGGGAAGACUAGC 792 1241-1318 Sequence strand AGCCGAAAGGCUGC NR1H3-1249- Artificial 36 mer sense CAGGGCUGCAAGUGGAAUUAGC 793 1269-1346 Sequence strand AGCCGAAAGGCUGC NR1H3-1254- Artificial 36 mer sense CUGCAAGUGGAAUUCAUCAAGCA 794 1274-1351 Sequence strand GCCGAAAGGCUGC NR1H3-1255- Artificial 36 mer sense UGCAAGUGGAAUUCAUCAAAGC 795 1275-1352 Sequence strand AGCCGAAAGGCUGC NR1H3-1256- Artificial 36 mer sense GCAAGUGGAAUUCAUCAACAGCA 796 1276-1353 Sequence strand GCCGAAAGGCUGC NR1H3-1257- Artificial 36 mer sense CAAGUGGAAUUCAUCAACCAGCA 797 1277-1354 Sequence strand GCCGAAAGGCUGC NR1H3-1260- Artificial 36 mer sense GUGGAAUUCAUCAACCCCAAGCA 798 1280-1357 Sequence strand GCCGAAAGGCUGC NR1H3-1261- Artificial 36 mer sense UGGAAUUCAUCAACCCCAUAGCA 799 1281-1358 Sequence strand GCCGAAAGGCUGC NR1H3-1263- Artificial 36 mer sense GAAUUCAUCAACCCCAUCUAGCA 800 1283-1360 Sequence strand GCCGAAAGGCUGC NR1H3-1264- Artificial 36 mer sense AAUUCAUCAACCCCAUCUUAGCA 801 1284-1361 Sequence strand GCCGAAAGGCUGC NR1H3-1405- Artificial 36 mer sense UGCAGCACACAUAUGUGGAAGCA 802 1471-1502 Sequence strand GCCGAAAGGCUGC NR1H3-1409- Artificial 36 mer sense GCACACAUAUGUGGAAGCCAGCA 803 1475-1506 Sequence strand GCCGAAAGGCUGC NR1H3-1458- Artificial 36 mer sense CAUGACCGACUGAUGUUCCAGCA 804 1524-1555 Sequence strand GCCGAAAGGCUGC NR1H3-1464- Artificial 36 mer sense CGACUGAUGUUCCCACGGAAGCA 805 1530-1561 Sequence strand GCCGAAAGGCUGC NR1H3-1465- Artificial 36 mer sense GACUGAUGUUCCCACGGAUAGCA 806 1531-1562 Sequence strand GCCGAAAGGCUGC NR1H3-1467- Artificial 36 mer sense CUGAUGUUCCCACGGAUGCAGCA 807 1533-1564 Sequence strand GCCGAAAGGCUGC NR1H3-1469- Artificial 36 mer sense GAUGUUCCCACGGAUGCUAAGCA 808 1535-1566 Sequence strand GCCGAAAGGCUGC NR1H3-1470- Artificial 36 mer sense AUGUUCCCACGGAUGCUAAAGCA 809 1536-1567 Sequence strand GCCGAAAGGCUGC NR1H3-1480- Artificial 36 mer sense GGAUGCUAAUGAAACUGGUAGC 810 1546-1577 Sequence strand AGCCGAAAGGCUGC NR1H3-1482- Artificial 36 mer sense AUGCUAAUGAAACUGGUGAAGC 811 1548-1579 Sequence strand AGCCGAAAGGCUGC NR1H3-1524- Artificial 36 mer sense CACUCAGAGCAAGUGUUUGAGCA 812 1590-1621 Sequence strand GCCGAAAGGCUGC NR1H3-1594- Artificial 36 mer sense AUGUGCACGAAUGACUGUUAGC 813 1660-1691 Sequence strand AGCCGAAAGGCUGC NR1H3-1595- Artificial 36 mer sense UGUGCACGAAUGACUGUUCAGCA 814 1661-1692 Sequence strand GCCGAAAGGCUGC NR1H3-1596- Artificial 36 mer sense GUGCACGAAUGACUGUUCUAGCA 815 1662 Sequence strand GCCGAAAGGCUGC NR1H3-1670- Artificial 36 mer sense UAGAAGUGGAACAGACUGAAGC 816 1734 Sequence strand AGCCGAAAGGCUGC NR1H3-1672- Artificial 36 mer sense GAAGUGGAACAGACUGAGAAGC 817 1736 Sequence strand AGCCGAAAGGCUGC NR1H3-1673- Artificial 36 mer sense AAGUGGAACAGACUGAGAAAGC 818 1737 Sequence strand AGCCGAAAGGCUGC NR1H3-1674- Artificial 36 mer sense AGUGGAACAGACUGAGAAGAGC 819 1738 Sequence strand AGCCGAAAGGCUGC NR1H3-1675- Artificial 36 mer sense GUGGAACAGACUGAGAAGGAGC 820 1739-1766 Sequence strand AGCCGAAAGGCUGC NR1H3-1676- Artificial 36 mer sense UGGAACAGACUGAGAAGGGAGC 821 1740-1767 Sequence strand AGCCGAAAGGCUGC NR1H3-1678- Artificial 36 mer sense GAACAGACUGAGAAGGGCAAGC 822 1742-1769 Sequence strand AGCCGAAAGGCUGC NR1H3-1207- Artificial 36 mer sense UCCUCAAGGAUUUCAGUUAAGCA 823 1227 Sequence strand GCCGGGCUGC NR1H3-1220- Artificial 36 mer sense CAGUUAUAACCGGGAAGACAGCA 824 1240 Sequence strand GCCGGGCUGC NR1H3-1224- Artificial 36 mer sense UAUAACCGGGAAGACUUUGAGC 825 1244 Sequence strand AGCCGGGCUGC NR1H3-1244- Artificial 36 mer sense CAAAGCAGGGCUGCAAGUGAGCA 826 1264 Sequence strand GCCGGGCUGC NR1H3-1252- Artificial 36 mer sense GGCUGCAAGUGGAAUUCAUAGC 827 1272 Sequence strand AGCCGGGCUGC NR1H3-1259- Artificial 36 mer sense AGUGGAAUUCAUCAACCCCAGCA 828 1279 Sequence strand GCCGGGCUGC NR1H3-1265- Artificial 36 mer sense AUUCAUCAACCCCAUCUUCAGCA 829 1285 Sequence strand GCCGGGCUGC NR1H3-1266- Artificial 36 mer sense UUCAUCAACCCCAUCUUCGAGCA 830 1286 Sequence strand GCCGGGCUGC NR1H3-1429- Artificial 36 mer sense UGCAUGCCUACGUCUCCAUAGCA 831 1495 Sequence strand GCCGGGCUGC NR1H3-1433- Artificial 36 mer sense UGCCUACGUCUCCAUCCACAGCA 832 1499 Sequence strand GCCGGGCUGC NR1H3-1437- Artificial 36 mer sense UACGUCUCCAUCCACCAUCAGCA 833 1503 Sequence strand GCCGGGCUGC NR1H3-1439- Artificial 36 mer sense CGUCUCCAUCCACCAUCCCAGCA 834 1505 Sequence strand GCCGGGCUGC NR1H3-1446- Artificial 36 mer sense AUCCACCAUCCCCAUGACCAGCA 835 1512 Sequence strand GCCGGGCUGC NR1H3-1463- Artificial 36 mer sense CCGACUGAUGUUCCCACGGAGCA 836 1529 Sequence strand GCCGGGCUGC NR1H3-1475- Artificial 36 mer sense CCCACGGAUGCUAAUGAAAAGCA 837 1541 Sequence strand GCCGGGCUGC NR1H3-1479- Artificial 36 mer sense CGGAUGCUAAUGAAACUGGAGC 838 1545 Sequence strand AGCCGGGCUGC NR1H3-1481- Artificial 36 mer sense GAUGCUAAUGAAACUGGUGAGC 839 1547 Sequence strand AGCCGGGCUGC NR1H3-1485- Artificial 36 mer sense CUAAUGAAACUGGUGAGCCAGCA 840 1551 Sequence strand GCCGGGCUGC NR1H3-1515- Artificial 36 mer sense AGCAGCGUCCACUCAGAGCAGCA 841 1581 Sequence strand GCCGGGCUGC NR1H3-1517- Artificial 36 mer sense CAGCGUCCACUCAGAGCAAAGCA 842 1583 Sequence strand GCCGGGCUGC NR1H3-1518- Artificial 36 mer sense AGCGUCCACUCAGAGCAAGAGCA 843 1584 Sequence strand GCCGGGCUGC NR1H3-1533- Artificial 36 mer sense CAAGUGUUUGCACUGCGUCAGCA 844 1599 Sequence strand GCCGGGCUGC NR1H3-1535- Artificial 36 mer sense AGUGUUUGCACUGCGUCUGAGCA 845 1601 Sequence strand GCCGGGCUGC NR1H3-1545- Artificial 36 mer sense CUGCGUCUGCAGGACAAAAAGCA 846 1611 Sequence strand GCCGGGCUGC NR1H3-1554- Artificial 36 mer sense CAGGACAAAAAGCUCCCACAGCA 847 1620 Sequence strand GCCGGGCUGC NR1H3-1581- Artificial 36 mer sense UCUGAGAUCUGGGAUGUGCAGC 848 1647 Sequence strand AGCCGGGCUGC NR1H3-1586- Artificial 36 mer sense GAUCUGGGAUGUGCACGAAAGC 849 1652 Sequence strand AGCCGGGCUGC NR1H3-1587- Artificial 36 mer sense AUCUGGGAUGUGCACGAAUAGC 850 1653 Sequence strand AGCCGGGCUGC NR1H3-1588- Artificial 36 mer sense UCUGGGAUGUGCACGAAUGAGC 851 1654 Sequence strand AGCCGGGCUGC NR1H3-1663- Artificial 36 mer sense UGCCUCCUAGAAGUGGAACAGCA 852 1727 Sequence strand GCCGGGCUGC NR1H3-1671- Artificial 36 mer sense AGAAGUGGAACAGACUGAGAGC 853 1735 Sequence strand AGCCGGGCUGC NR1H3-1684- Artificial 36 mer sense ACUGAGAAGGGCAAACAUUAGC 854 1748 Sequence strand AGCCGGGCUGC NR1H3-1731- Artificial 36 mer sense GUGGCAUUAAAAGAGAGUCAGC 855 1795 Sequence strand AGCCGGGCUGC NR1H3-1732- Artificial 36 mer sense UGGCAUUAAAAGAGAGUCAAGC 856 1796 Sequence strand AGCCGGGCUGC NR1H3-763- Artificial 22 mer UUGUUCUUCUGACAGGACACGG 857 783-860 Sequence antisense strand NR1H3-765- Artificial 22 mer UUCUGUUCUUCUGACAGGACGG 858 785-862 Sequence antisense strand NR1H3-767- Artificial 22 mer UGAUCUGUUCUUCUGACAGGGG 859 787-864 Sequence antisense strand NR1H3-768- Artificial 22 mer UGGAUCUGUUCUUCUGACAGGG 860 788-865 Sequence antisense strand NR1H3-769- Artificial 22 mer UCGGAUCUGUUCUUCUGACAGG 861 789-866 Sequence antisense strand NR1H3-794- Artificial 22 mer UCUCUUGCCGCUUCAGUUUCGG 862 814-891 Sequence antisense strand NR1H3-1152- Artificial 22 mer UAUGUCUCCAGAAGCAUCACGG 863 1172-1249 Sequence antisense strand NR1H3-1189- Artificial 22 mer UAAGGUGAUACUCUCACUCCGG 864 1209-1286 Sequence antisense strand NR1H3-1195- Artificial 22 mer UUUGAGGAAGGUGAUACUCUGG 865 1215-1292 Sequence antisense strand NR1H3-1200- Artificial 22 mer UAAUCCUUGAGGAAGGUGAUGG 866 1220-1297 Sequence antisense strand NR1H3-1201- Artificial 22 mer UAAAUCCUUGAGGAAGGUGAGG 867 1221-1298 Sequence antisense strand NR1H3-1202- Artificial 22 mer UGAAAUCCUUGAGGAAGGUGGG 868 1222-1299 Sequence antisense strand NR1H3-1203- Artificial 22 mer UUGAAAUCCUUGAGGAAGGUGG 869 1223-1300 Sequence antisense strand NR1H3-1204- Artificial 22 mer UCUGAAAUCCUUGAGGAAGGGG 870 1224-1301 Sequence antisense strand NR1H3-1205- Artificial 22 mer UACUGAAAUCCUUGAGGAAGGG 871 1225-1302 Sequence antisense strand NR1H3-1206- Artificial 22 mer UAACUGAAAUCCUUGAGGAAGG 872 1226-1303 Sequence antisense strand NR1H3-1208- Artificial 22 mer UAUAACUGAAAUCCUUGAGGGG 873 1228-1305 Sequence antisense strand NR1H3-1209- Artificial 22 mer UUAUAACUGAAAUCCUUGAGGG 874 1229-1306 Sequence antisense strand NR1H3-1210- Artificial 22 mer UUUAUAACUGAAAUCCUUGAGG 875 1230-1307 Sequence antisense strand NR1H3-1211- Artificial 22 mer UGUUAUAACUGAAAUCCUUGGG 876 1231-1308 Sequence antisense strand NR1H3-1212- Artificial 22 mer UGGUUAUAACUGAAAUCCUUGG 877 1232-1309 Sequence antisense strand NR1H3-1213- Artificial 22 mer UCGGUUAUAACUGAAAUCCUGG 878 1233-1310 Sequence antisense strand NR1H3-1214- Artificial 22 mer UCCGGUUAUAACUGAAAUCCGG 879 1234-1311 Sequence antisense strand NR1H3-1221- Artificial 22 mer UAGUCUUCCCGGUUAUAACUGG 880 1241-1318 Sequence antisense strand NR1H3-1249- Artificial 22 mer UAAUUCCACUUGCAGCCCUGGG 881 1269-1346 Sequence antisense strand NR1H3-1254- Artificial 22 mer UUGAUGAAUUCCACUUGCAGGG 882 1274-1351 Sequence antisense strand NR1H3-1255- Artificial 22 mer UUUGAUGAAUUCCACUUGCAGG 883 1275-1352 Sequence antisense strand NR1H3-1256- Artificial 22 mer UGUUGAUGAAUUCCACUUGCGG 884 1276-1353 Sequence antisense strand NR1H3-1257- Artificial 22 mer UGGUUGAUGAAUUCCACUUGGG 885 1277-1354 Sequence antisense strand NR1H3-1260- Artificial 22 mer UUGGGGUUGAUGAAUUCCACGG 886 1280-1357 Sequence antisense strand NR1H3-1261- Artificial 22 mer UAUGGGGUUGAUGAAUUCCAGG 887 1281-1358 Sequence antisense strand NR1H3-1263- Artificial 22 mer UAGAUGGGGUUGAUGAAUUCGG 888 1283-1360 Sequence antisense strand NR1H3-1264- Artificial 22 mer UAAGAUGGGGUUGAUGAAUUGG 889 1284-1361 Sequence antisense strand NR1H3-1405- Artificial 22 mer UUCCACAUAUGUGUGCUGCAGG 890 1471-1502 Sequence antisense strand NR1H3-1409- Artificial 22 mer UGGCUUCCACAUAUGUGUGCGG 891 1475-1506 Sequence antisense strand NR1H3-1458- Artificial 22 mer UGGAACAUCAGUCGGUCAUGGG 892 1524-1555 Sequence antisense strand NR1H3-1464- Artificial 22 mer UUCCGUGGGAACAUCAGUCGGG 893 1530-1561 Sequence antisense strand NR1H3-1465- Artificial 22 mer UAUCCGUGGGAACAUCAGUCGG 894 1531-1562 Sequence antisense strand NR1H3-1467- Artificial 22 mer UGCAUCCGUGGGAACAUCAGGG 895 1533-1564 Sequence antisense strand NR1H3-1469- Artificial 22 mer UUAGCAUCCGUGGGAACAUCGG 896 1535-1566 Sequence antisense strand NR1H3-1470- Artificial 22 mer UUUAGCAUCCGUGGGAACAUGG 897 1536-1567 Sequence antisense strand NR1H3-1480- Artificial 22 mer UACCAGUUUCAUUAGCAUCCGG 898 1546-1577 Sequence antisense strand NR1H3-1482- Artificial 22 mer UUCACCAGUUUCAUUAGCAUGG 899 1548-1579 Sequence antisense strand NR1H3-1524- Artificial 22 mer UCAAACACUUGCUCUGAGUGGG 900 1590-1621 Sequence antisense strand NR1H3-1594- Artificial 22 mer UAACAGUCAUUCGUGCACAUGG 901 1660-1691 Sequence antisense strand NR1H3-1595- Artificial 22 mer UGAACAGUCAUUCGUGCACAGG 902 1661-1692 Sequence antisense strand NR1H3-1596- Artificial 22 mer UAGAACAGUCAUUCGUGCACGG 903 1662 Sequence antisense strand NR1H3-1670- Artificial 22 mer UUCAGUCUGUUCCACUUCUAGG 904 1734 Sequence antisense strand NR1H3-1672- Artificial 22 mer UUCUCAGUCUGUUCCACUUCGG 905 1736 Sequence antisense strand NR1H3-1673- Artificial 22 mer UUUCUCAGUCUGUUCCACUUGG 906 1737 Sequence antisense strand NR1H3-1674- Artificial 22 mer UCUUCUCAGUCUGUUCCACUGG 907 1738 Sequence antisense strand NR1H3-1675- Artificial 22 mer UCCUUCUCAGUCUGUUCCACGG 908 1739-1766 Sequence antisense strand NR1H3-1676- Artificial 22 mer UCCCUUCUCAGUCUGUUCCAGG 909 1740-1767 Sequence antisense strand NR1H3-1678- Artificial 22 mer UUGCCCUUCUCAGUCUGUUCGG 910 1742-1769 Sequence antisense strand NR1H3-1207- Artificial 22 mer UUAACUGAAAUCCUUGAGGAGG 911 1227 Sequence antisense strand NR1H3-1220- Artificial 22 mer UGUCUUCCCGGUUAUAACUGGG 912 1240 Sequence antisense strand NR1H3-1224- Artificial 22 mer UCAAAGUCUUCCCGGUUAUAGG 913 1244 Sequence antisense strand NR1H3-1244- Artificial 22 mer UCACUUGCAGCCCUGCUUUGGG 914 1264 Sequence antisense strand NR1H3-1252- Artificial 22 mer UAUGAAUUCCACUUGCAGCCGG 915 1272 Sequence antisense strand NR1H3-1259- Artificial 22 mer UGGGGUUGAUGAAUUCCACUGG 916 1279 Sequence antisense strand Artificial 22 mer UGAAGAUGGGGUUGAUGAAUGG 917 NR1H3-1265- Sequence antisense 1285 strand Artificial 22 mer UCGAAGAUGGGGUUGAUGAAGG 918 NR1H3-1266- Sequence antisense 1286 strand NR1H3-1429- Artificial 22 mer UAUGGAGACGUAGGCAUGCAGG 919 1495 Sequence antisense strand NR1H3-1433- Artificial 22 mer UGUGGAUGGAGACGUAGGCAGG 920 1499 Sequence antisense strand NR1H3-1437- Artificial 22 mer UGAUGGUGGAUGGAGACGUAGG 921 1503 Sequence antisense strand NR1H3-1439- Artificial 22 mer UGGGAUGGUGGAUGGAGACGGG 922 1505 Sequence antisense strand NR1H3-1446- Artificial 22 mer UGGUCAUGGGGAUGGUGGAUGG 923 1512 Sequence antisense strand NR1H3-1463- Artificial 22 mer UCCGUGGGAACAUCAGUCGGGG 924 1529 Sequence antisense strand NR1H3-1475- Artificial 22 mer UUUUCAUUAGCAUCCGUGGGGG 925 1541 Sequence antisense strand NR1H3-1479- Artificial 22 mer UCCAGUUUCAUUAGCAUCCGGG 926 1545 Sequence antisense strand NR1H3-1481- Artificial 22 mer UCACCAGUUUCAUUAGCAUCGG 927 1547 Sequence antisense strand NR1H3-1485- Artificial 22 mer UGGCUCACCAGUUUCAUUAGGG 928 1551 Sequence antisense strand NR1H3-1515- Artificial 22 mer UGCUCUGAGUGGACGCUGCUGG 929 1581 Sequence antisense strand NR1H3-1517- Artificial 22 mer UUUGCUCUGAGUGGACGCUGGG 930 1583 Sequence antisense strand NR1H3-1518- Artificial 22 mer UCUUGCUCUGAGUGGACGCUGG 931 1584 Sequence antisense strand NR1H3-1533- Artificial 22 mer UGACGCAGUGCAAACACUUGGG 932 1599 Sequence antisense strand NR1H3-1535- Artificial 22 mer UCAGACGCAGUGCAAACACUGG 933 1601 Sequence antisense strand NR1H3-1545- Artificial 22 mer UUUUUGUCCUGCAGACGCAGGG 934 1611 Sequence antisense strand NR1H3-1554- Artificial 22 mer UGUGGGAGCUUUUUGUCCUGGG 935 1620 Sequence antisense strand NR1H3-1581- Artificial 22 mer UGCACAUCCCAGAUCUCAGAGG 936 1647 Sequence antisense strand NR1H3-1586- Artificial 22 mer UUUCGUGCACAUCCCAGAUCGG 937 1652 Sequence antisense strand NR1H3-1587- Artificial 22 mer UAUUCGUGCACAUCCCAGAUGG 938 1653 Sequence antisense strand NR1H3-1588- Artificial 22 mer UCAUUCGUGCACAUCCCAGAGG 939 1654 Sequence antisense strand NR1H3-1663- Artificial 22 mer UGUUCCACUUCUAGGAGGCAGG 940 1727 Sequence antisense strand NR1H3-1671- Artificial 22 mer UCUCAGUCUGUUCCACUUCUGG 941 1735 Sequence antisense strand NR1H3-1684- Artificial 22 mer UAAUGUUUGCCCUUCUCAGUGG 942 1748 Sequence antisense strand NR1H3-1731- Artificial 22 mer UGACUCUCUUUUAAUGCCACGG 943 1795 Sequence antisense strand NR1H3-1732- Artificial 22 mer UUGACUCUCUUUUAAUGCCAGG 944 1796 Sequence antisense strand NR1H3-763- Artificial Modified [mGs][mU][mG][mU][mC][mC][mU] 945 783-860 Sequence sense strand [fG][fU][fC][fA][mG][mA][mA][mG] [mA][mA][mC][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-765- Artificial Modified [mGs][mU][mC][mC][mU][mG][mU] 946 785-862 Sequence sense strand [fC][fA][fG][fA][mA][mG][mA][mA] [mC][mA][mG][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-767- Artificial Modified [mCs][mC][mU][mG][mU][mC][mA] 947 787-864 Sequence sense strand [fG][fA][fA][fG][mA][mA][mC][mA] [mG][mA][mU][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-768- Artificial Modified [mCs][mU][mG][mU][mC][mA][mG] 948 788-865 Sequence sense strand [fA][fA][fG][fA][mA][mC][mA][mG] [mA][mU][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-769- Artificial Modified [mUs][mG][mU][mC][mA][mG][mA] 949 789-866 Sequence sense strand [fA][fG][fA][fA][mC][mA][mG][mA] [mU][mC][mC][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-794- Artificial Modified [mGs][mA][mA][mA][mC][mU][mG] 950 814-891 Sequence sense strand [fA][fA][fG][fC][mG][mG][mC][mA] [mA][mG][mA][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1152- Artificial Modified [mGs][mU][mG][mA][mU][mG][mC] 951 1172-1249 Sequence sense strand [fU][fU][fC][fU][mG][mG][mA][mG] [mA][mC][mA][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1189- Artificial Modified [mGs][mG][mA][mG][mU][mG][mA] 952 1209-1286 Sequence sense strand [fG][fA][fG][fU][mA][mU][mC][mA] [mC][mC][mU][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1195- Artificial Modified [mAs][mG][mA][mG][mU][mA][mU] 953 1215-1292 Sequence sense strand [fC][fA][fC][fC][mU][mU][mC][mC] [mU][mC][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1200- Artificial Modified [mAs][mU][mC][mA][mC][mC][mU] 954 1220-1297 Sequence sense strand [fU][fC][fC][fU][mC][mA][mA][mG] [mG][mA][mU][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1201- Artificial Modified [mUs][mC][mA][mC][mC][mU][mU] 955 1221-1298 Sequence sense strand [fC][fC][fU][fC][mA][mA][mG][mG] [mA][mU][mU][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1202- Artificial Modified [mCs][mA][mC][mC][mU][mU][mC] 956 1222-1299 Sequence sense strand [fC][fU][fC][fA][mA][mG][mG][mA] [mU][mU][mU][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1203- Artificial Modified [mAs][mC][mC][mU][mU][mC][mC] 957 1223-1300 Sequence sense strand [fU][fC][fA][fA][mG][mG][mA][mU] [mU][mU][mC][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1204- Artificial Modified [mCs][mC][mU][mU][mC][mC][mU] 958 1224-1301 Sequence sense strand [fC][fA][fA][fG][mG][mA][mU][mU] [mU][mC][mA][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1205- Artificial Modified [mCs][mU][mU][mC][mC][mU][mC] 959 1225-1302 Sequence sense strand [fA][fA][fG][fG][mA][mU][mU][mU] [mC][mA][mG][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1206- Artificial Modified [mUs][mU][mC][mC][mU][mC][mA] 960 1226-1303 Sequence sense strand [fA][fG][fG][fA][mU][mU][mU][mC] [mA][mG][mU][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1207- Artificial Modified [mUs][mC][mC][mU][mC][mA][mAf 961 1227 Sequence sense strand [fG][fG][fA][fU][mU][mU][mC][mA] [mG][mU][mU][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1208- Artificial Modified [mCs][mC][mU][mC][mA][mA][mG] 962 1228-1305 Sequence sense strand [fG][fA][fU][fU][mU][mC][mA][mG] [mU][mU][mA][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1209- Artificial Modified [mCs][mU][mC][mA][mA][mG][mG] 963 1229-1306 Sequence sense strand [fA][fU][fU][fU][mC][mA][mG][mU] [mU][mA][mU][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1210- Artificial Modified [mUs][mC][mA][mA][mG][mG][mA] 964 1230-1307 Sequence sense strand [fU][fU][fU][fC][mA][mG][mU][mU] [mA][mU][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1211- Artificial Modified [mCs][mA][mA][mG][mG][mA][mU] 965 1231-1308 Sequence sense strand [fU][fU][fC][fA][mG][mU][mU][mA] [mU][mA][mA][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC NR1H3-1212- Artificial Modified [mAs][mA][mG][mG][mA][mU][mU] 966 1232-1309 Sequence sense strand [fU][fC][fA][fG][mU][mU][mA][mU] [mA][mA][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1213- Artificial Modified [mAs][mG][mG][mA][mU][mU][mU] 967 1233-1310 Sequence sense strand [fC][fA][fG][fU][mU][mA][mU][mA] [mA][mC][mC][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1214- Artificial Modified [mGs][mG][mA][mU][mU][mU][mC] 968 1234-1311 Sequence sense strand [fA][fG][fU][fU][mA][mU][mA][mA] [mC][mC][mG][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1220 Artificial Modified [mCs][mA][mG][mU][mU][mA][mU] 969 Sequence sense strand [fA][fA][fC][fC][mG][mG][mG][mA] [mA][mG][mA][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1221- Artificial Modified [mAs][mG][mU][mU][mA][mU][mA] 970 1241-1318 Sequence sense strand [fA][fC][fC][fG][mG][mG][mA][mA] [mG][mA][mC][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1224- Artificial Modified [mUs][mA][mU][mA][mA][mC][mC] 971 1244 Sequence sense strand [mU][mU][mU][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1244- Artificial Modified [mCs][mA][mA][mA][mG][mC][mA] 972 1264 Sequence sense strand [fG][fG][fG][fC][mU][mG][mC][mA] [mA][mG][mU][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1249- Artificial Modified [mCs][mA][mG][mG][mG][mC][mU] 973 1269-1346 Sequence sense strand [fG][fC][fA][fA][mG][mU][mG][mG] [mA][mA][mU][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1252- Artificial Modified [mGs][mG][mC][mU][mG][mC][mA] 974 1272 Sequence sense strand [fA][fG][fU][fG][mG][mA][mA][mU] [mU][mC][mA][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1254- Artificial Modified [mCs][mU][mG][mC][mA][mA][mG] 975 1274-1351 Sequence sense strand [fU][fG][fG][fA][mA][mU][mU][mC] [mA][mU][mC][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1255- Artificial Modified [mUs][mG][mC][mA][mA][mG][mU] 976 1275-1352 Sequence sense strand [fG][fG][fA][fA][mU][mU][mC][mA] [mU][mC][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1256- Artificial Modified [mGs][mC][mA][mA][mG][mU][mG] 977 1276-1353 Sequence sense strand [fG][fA][fA][fU][mU][mC][mA][mU] [mC][mA][mA][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1257- Artificial Modified [mCs][mA][mA][mG][mU][mG][mG] 978 1277-1354 Sequence sense strand [fA][fA][fU][fU][mC][mA][mU][mC] [mA][mA][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1259 Artificial Modified [mAs][mG][mU][mG][mG][mA][mA] 979 Sequence sense strand [fU][fU][fC][fA][mU][mC][mA][mA] [mC][mC][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1260- Artificial Modified [mGs][mU][mG][mG][mA][mA][mU][f 980 1280-1357 Sequence sense strand [fU][fC][fA][fU][mC][mA][mA][mC] [mC][mC][mC][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1261- Artificial Modified [mUs][mG][mG][mA][mA][mU][mU] 981 1281-1358 Sequence sense strand [fC][fA][fU][fC][mA][mA][mC][mC] [mC][mC][mA][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAclrademA-GalNAclrademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1263- Artificial Modified [mGs][mA][mA][mU][mU][mC][mA] 982 1283-1360 Sequence sense strand [fU][fC][fA][fA][mC][mC][mC][mC] [mA][mU][mC][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1264- Artificial Modified [mAs][mA][mU][mU][mC][mA][mU] 983 1284-1361 Sequence sense strand [fC][fA][fA][fC][mC][mC][mC][mA] [mU][mC][mU][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1265- Artificial Modified [mAs][mU][mU][mC][mA][mU][mC] 984 1285 Sequence sense strand [fA][fA][fC][fC][mC][mC][mA][mU] [mC][mU][mU][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1266- Artificial Modified [mUs][mU][mC][mA][mU][mC][mA] 985 1286 Sequence sense strand [fA][fC][fC][fC][mC][mA][mU][mC] [mU][mU][mC][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1405- Artificial Modified [mUs][mG][mC][mA][mG][mC][mA] 986 1471-1502 Sequence sense strand [fC][fA][fC][fA][mU][mA][mU][mG] [mU][mG][mG][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1409- Artificial Modified [mGs][mC][mA][mC][mA][mC][mA] 987 1475-1506 Sequence sense strand [fU][fA][fU][fG][mU][mG][mG][mA] [mA][mG][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1429- Artificial Modified [mUs][mG][mC][mA][mU][mG][mC] 988 1495 Sequence sense strand [fC][fU][fA][fC][mG][mU][mC][mU] [mC][mC][mA][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1433- Artificial Modified [mUs][mG][mC][mC][mU][mA][mC] 989 1499 Sequence sense strand [fG][fU][fC][fU][mC][mC][mA][mU] [mC][mC][mA][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1437- Artificial Modified [mUs][mA][mC][mG][mU][mC][mU] 990 1503 Sequence sense strand [fC][fC][fA][fU][mC][mC][mA][mC] [mC][mA][mU][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1439- Artificial Modified [mCs][mG][mU][mC][mU][mC][mC] 991 1505 Sequence sense strand [fA][fU][fC][fC][mA][mC][mC][mA] [mU][mC][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1446- Artificial Modified [mAs][mU][mC][mC][mA][mC][mC] 992 1512 Sequence sense strand [fA][fU][fC][fC][mC][mC][mA][mU] [mG][mA][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1458- Artificial Modified [mCs][mA][mU][mG][mA][mC][mC] 993 1524-1555 Sequence sense strand [fG][fA][fC][fU][mG][mA][mU][mG] [mU][mU][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1463- Artificial Modified [mCs][mC][mG][mA][mC][mU][mG] 994 1529 Sequence sense strand [fA][fU][fG][fU][mU][mC][mC][mC] [mA][mC][mG][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1464- Artificial Modified [mCs][mG][mA][mC][mU][mG][mA] 995 1530-1561 Sequence sense strand [fU][fG][fU][fU][mC][mC][mC][mA] [mC][mG][mG][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1465- Artificial Modified [mGs][mA][mC][mU][mG][mA][mU] 996 1531-1562 Sequence sense strand [fG][fU][fU][fC][mC][mC][mA][mC] [mG][mG][mA][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1467- Artificial Modified [mCs][mU][mG][mA][mU][mG][mU] 997 1533-1564 Sequence sense strand [fU][fC][fC][fC][mA][mC][mG][mG] [mA][mU][mG][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1469- Artificial Modified [mGs][mA][mU][mG][mU][mU][mC] 998 1535-1566 Sequence sense strand [fC][fC][fA][fC][mG][mG][mA][mU] [mG][mC][mU][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1470- Artificial Modified [mAs][mU][mG][mU][mU][mC][mC] 999 1536-1567 Sequence sense strand [fC][fA][fC][fG][mG][mA][mU][mG] [mC][mU][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1475- Artificial Modified [mCs][mC][mC][mA][mC][mG][mG] 1000 1541 Sequence sense strand [fA][fU][fG][fC][mU][mA][mA][mU] [mG][mA][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1479- Artificial Modified [mCs][mG][mG][mA][mU][mG][mC] 1001 1545 Sequence sense strand [fU][fA][fA][fU][mG][mA][mA][mA] [mC][mU][mG][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1480- Artificial Modified [mGs][mG][mA][mU][mG][mC][mU] 1002 1546-1577 Sequence sense strand [fA][fA][fU][fG][mA][mA][mA][mC] [mU][mG][mG][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1481- Artificial Modified [mGs][mA][mU][mG][mC][mU][mA] 1003 1547 Sequence sense strand [fA][fU][fG][fA][mA][mA][mC][mU] [mG][mG][mU][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1482- Artificial Modified [mAs][mU][mG][mC][mU][mA][mA] 1004 1548-1579 Sequence sense strand [fU][fG][fA][fA][mA][mC][mU][mG] [mG][mU][mG][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1485- Artificial Modified [mCs][mU][mA][mA][mU][mG][mA] 1005 1551 Sequence sense strand [fA][fA][fC][fU][mG][mG][mU][mG] [mA][mG][mC][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1515- Artificial Modified [mAs][mG][mC][mA][mG][mC][mG] 1006 1581 Sequence sense strand [fU][fC][fC][fA][mC][mU][mC][mA] [mG][mA][mG][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1517- Artificial Modified [mCs][mA][mG][mC][mG][mU][mC] 1007 1583 Sequence sense strand [fC][fA][fC][fU][mC][mA][mG][mA] [mG][mC][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1518- Artificial Modified [mAs][mG][mC][mG][mU][mC][mC] 1008 1584 Sequence sense strand [fA][fC][fU][fC][mA][mG][mA][mG] [mC][mA][mA][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1524- Artificial Modified [mCs][mA][mC][mU][mC][mA][mG] 1009 1590-1621 Sequence sense strand [fA][fG][fC][fA][mA][mG][mU][mG] [mU][mU][mU][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1533- Artificial Modified [mCs][mA][mA][mG][mU][mG][mU] 1010 1599 Sequence sense strand [fU][fU][fG][fC][mA][mC][mU][mG] [mC][mG][mU][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1535- Artificial Modified [mAs][mG][mU][mG][mU][mU][mU] 1011 1601 Sequence sense strand [fG][fC][fA][fC][mU][mG][mC][mG] [mU][mC][mU][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1545- Artificial Modified [mCs][mU][mG][mC][mG][mU][mC] 1012 1611 Sequence sense strand [fU][fG][fC][fA][mG][mG][mA][mC] [mA][mA][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1554- Artificial Modified [mCs][mA][mG][mG][mA][mC][mA] 1013 1620 Sequence sense strand [fA][fA][fA][fA][mG][mC][mU][mC] [mC][mC][mA][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1581- Artificial Modified [mUs][mC][mU][mG][mA][mG][mA] 1014 1647 Sequence sense strand [fU][fC][fU][fG][mG][mG][mA][mU] [mG][mU][mG][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1586- Artificial Modified [mGs][mA][mU][mC][mU][mG][mG] 1015 1652 Sequence sense strand [fG][fA][fU][fG][mU][mG][mC][mA] [mC][mG][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1587- Artificial Modified [mAs][mU][mC][mU][mG][mG][mG] 1016 1653 Sequence sense strand [fA][fU][fG][fU][mG][mC][mA][mC] [mG][mA][mA][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1588- Artificial Modified [mUs][mC][mU][mG][mG][mG][mA] 1017 1654 Sequence sense strand [fU][fG][fU][fG][mC][mA][mC][mG] [mA][mA][mU][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1594- Artificial Modified [mAs][mU][mG][mU][mG][mC][mA] 1018 1660-1691 Sequence sense strand [fC][fG][fA][fA][mU][mG][mA][mC] [mU][mG][mU][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1595- Artificial Modified [mUs][mG][mU][mG][mC][mA][mC] 1019 1661-1692 Sequence sense strand [fG][fA][fA][fU][mG][mA][mC][mU] [mG][mU][mU][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1596- Artificial Modified [mGs][mU][mG][mC][mA][mC][mG] 1020 1662 Sequence sense strand [fA][fA][fU][fG][mA][mC][mU][mG] [mU][mU][mC][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1663- Artificial Modified [mUs][mG][mC][mC][mU][mC][mC] 1021 1727 Sequence sense strand [fU][fA][fG][fA][mA][mG][mU][mG] [mG][mA][mA][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1670- Artificial Modified [mUs][mA][mG][mA][mA][mG][mU] 1022 1734 Sequence sense strand [fG][fG][fA][fA][mC][mA][mG][mA] [mC][mU][mG][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1671- Artificial Modified [mAs][mG][mA][mA][mG][mU][mG] 1023 1735 Sequence sense strand [fG][fA][fA][fC][mA][mG][mA][mC] [mU][mG][mA][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1672- Artificial Modified [mGs][mA][mA][mG][mU][mG][mG] 1024 1736 Sequence sense strand [fA][fA][fC][fA][mG][mA][mC][mU] [mG][mA][mG][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1673- Artificial Modified [mAs][mA][mG][mU][mG][mG][mA] 1025 1737 Sequence sense strand [fA][fC][fA][fG][mA][mC][mU][mG] [mA][mG][mA][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1674- Artificial Modified [mAs][mG][mU][mG][mG][mA][mA] 1026 1738 Sequence sense strand [fC][fA][fG][fA][mC][mU][mG][mA] [mG][mA][mA][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1675- Artificial Modified [mGs][mU][mG][mG][mA][mA][mC] 1027 1739-1766 Sequence sense strand [fA][fG][fA][fC][mU][mG][mA][mG] [mA][mA][mG][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1676- Artificial Modified [mUs][mG][mG][mA][mA][mC][mA] 1028 1740-1767 Sequence sense strand [fG][fA][fC][fU][mG][mA][mG][mA] [mA][mG][mG][mG][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1678- Artificial Modified [mGs][mA][mA][mC][mA][mG][mA] 1029 1742-1769 Sequence sense strand [fC][fU][fG][fA][mG][mA][mA][mG] [mG][mG][mC][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1684- Artificial Modified [mAs][mC][mU][mG][mA][mG][mA] 1030 1748 Sequence sense strand [fA][fG][fG][fG][mC][mA][mA][mA] [mC][mA][mU][mU][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1731- Artificial Modified [mGs][mU][mG][mG][mC][mA][mU] 1031 1795 Sequence sense strand [fU][fA][fA][fA][mA][mG][mA][mG] [mA][mG][mU][mC][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-1732- Artificial Modified [mUs][mG][mG][mC][mA][mU][mU] 1032 1796 Sequence sense strand [fA][fA][fA][fA][mG][mA][mG][mA] [mG][mU][mC][mA][mA][mG][mC][mA] [mG][mC][mC][mG][ademA- GalNAc][ademA-GalNAc][ademA- GalNAc][mG][mG][mC][mU][mG][mC] NR1H3-763- Artificial Modified [MePhosphonate-4O- 1033 783-860 Sequence antisense mUs][fUs][fGs][fU][fU][mC][fU][mU] strand [mC][fU][mG][mA][mC][fA][mG][mG] [mA][mC][mA][mCs][mGs][mG] NR1H3-765- Artificial Modified [MePhosphonate-4O- 1034 785-862 Sequence antisense mUs][fUs][fCs][fU][fG][mU][fU][mC] strand [mU][fU][mC][mU][mG][fA][mC][mA] [mG][mG][mA][mCs][mGs][mG] NR1H3-767- Artificial Modified [MePhosphonate-4O- 1035 787-864 Sequence antisense mUs][fGs][fAs][fU][fC][mU][fG][mU] strand [mU][fC][mU][mU][mC][fU][mG][mA] [mC][mA][mG][mGs][mGs][mG] NR1H3-768- Artificial Modified [MePhosphonate-4O- 1036 788-865 Sequence antisense mUs][fGs][fGs][fA][fU][mC][fU][mG] strand [mU][fU][mC][mU][mU][fC][mU][mG] [mA][mC][mA][mGs][mGs][mG] NR1H3-769- Artificial Modified [MePhosphonate-4O- 1037 789-866 Sequence antisense mUs][fCs][fG][mG][fA][mU][fC][mU] strand [mG][fU][mU][mC][mU][fU][mC][mU] [mG][mA][mC][mAs][mGs][mG] NR1H3-794- Artificial Modified [MePhosphonate-4O- 1038 814-891 Sequence antisense mUs][fCs][fUs][fC][fU][mU][fG][mC] strand [mC][fG][mC][mU][mU][fC][mA][mG] [mU][mU][mU][mCs][mGs][mG] NR1H3-1152- Artificial Modified [MePhosphonate-4O- 1039 1172-1249 Sequence antisense [mUs][fAs][fUs][fG][fU][mC][fU][mC] strand [mC][fA][mG][mA][mA][fG][mC][mA] [mU][mC][mA][mCs][mGs][mG] NR1H3-1189- Artificial Modified [MePhosphonate-4O- 1040 1209-1286 Sequence antisense mUs][fAs][fAs][fG][fG][mU][fG][mA] strand [mU][fA][mC][mU][mC][fU][mC][mA] [mC][mU][mC][mCs][mGs][mG] NR1H3-1195- Artificial Modified [MePhosphonate-4O- 1041 1215-1292 Sequence antisense mUs][fUs][fUs][fG][fA][mG][fG][mA] strand [mA][fG][mG][mU][mG][fA][mU][mA] [mC][mU][mC][mUs][mGs][mG] NR1H3-1200- Artificial Modified [MePhosphonate-4O- 1042 1220-1297 Sequence antisense mUs][fAs][fAs][fU][fC][mC][fU][mU] strand [mG][fA][mG][mG][mA][fA][mG][mG] [mU][mG][mA][mUs][mGs][mG] NR1H3-1201- Artificial Modified [MePhosphonate-4O- 1043 1221-1298 Sequence antisense mUs][fAs][fAs][fA][fU][mC][fC][mU] strand [mU][fG][mA][mG][mG][fA][mA][mG] [mG][mU][mG][mAs][mGs][mG] NR1H3-1202- Artificial Modified [MePhosphonate-4O- 1044 1222-1299 Sequence antisense mUs][fGs][fAs][fA][fA][mU][fC][mC] strand [mU][fU][mG][mA][mG][fG][mA][mA] [mG][mG][mU][mGs][mGs][mG] NR1H3-1203- Artificial Modified [MePhosphonate-4O- 1045 1223-1300 Sequence antisense mUs][fUs][fGs][fA][fA][mA][fU][mC] strand [mC][fU][mU][mG][mA][fG][mG][mA] [mA][mG][mG][mUs][mGs][mG] NR1H3-1204- Artificial Modified [MePhosphonate-4O- 1046 1224-1301 Sequence antisense mUs][fCs][fUs][fG][fA][mA][fA][mU] strand [mC][fC][mU][mU][mG][fA][mG][mG] [mA][mA][mG][mGs][mGs][mG] NR1H3-1205- Artificial Modified [MePhosphonate-4O- 1047 1225-1302 Sequence antisense mUs][fAs][fCs][fU][fG][mA][fA][mA] strand [mU][fC][mC][mU][mU][fG][mA][mG] [mG][mA][mA][mGs][mGs][mG] NR1H3-1206- Artificial Modified [MePhosphonate-4O- 1048 1226-1303 Sequence antisense mUs][fAs][fAs][fC][fU][mG][fA][mA] strand [mA][fU][mC][mC][mU][fU][mG][mA] [mG][mG][mA][mAs][mGs][mG] NR1H3-1207- Artificial Modified [MePhosphonate-4O- 1049 1227 Sequence antisense mUs][fUs][fAs][fA][fC][mU][fG][mA] strand [mA][fA][mU][mC][mC][fU][mU][mG] [mA][mG][mG][mAs][mGs][mG] NR1H3-1208- Artificial Modified [MePhosphonate-4O- 1050 1228-1305 Sequence antisense mUs][fAs][fUs][fA][fA][mC][fU][mG] strand [mA][fA][mA][mU][mC][fC][mU][mU] [mG][mA][mG][mGs][mGs][mG] NR1H3-1209- Artificial Modified [MePhosphonate-4O- 1051 1229-1306 Sequence antisense mUs][fUs][fAs][fU][fA][mA][fC][mU] strand [mG][fA][mA][mA][mU][fC][mC][mU] [mU][mG][mA][mGs][mGs][mG] NR1H3-1210- Artificial Modified [MePhosphonate-4O- 1052 1230-1307 Sequence antisense mUs][fUs][fUs][fA][fU][mA][fA][mC] strand [mU][fG][mA][mA][mA][fU][mC][mC] [mU][mU][mG][mAs][mGs][mG] NR1H3-1211- Artificial Modified [MePhosphonate-4O- 1053 1231-1308 Sequence antisense mUs][fGs][fUs][fU][fA][mU][fA][mA] strand [mC][fU][mG][mA][mA][fA][mU][mC] [mC][mU][mU][mGs][mGs][mG] NR1H3-1212- Artificial Modified [MePhosphonate-4O- 1054 1232-1309 Sequence antisense mUs][fGs][fGs][fU][fU][mA][fU][mA] strand [mA][fC][mU][mG][mA][fA][mA][mU] [mC][mC][mU][mUs][mGs][mG] NR1H3-1213- Artificial Modified [MePhosphonate-4O- 1055 1233-1310 Sequence antisense mUs][fCs][fGs][fG][fU][mU][fA][mU] strand [mA][fA][mC][mU][mG][fA][mA][mA] [mU][mC][mC][mUs][mGs][mG] NR1H3-1214- Artificial Modified [MePhosphonate-4O- 1056 1234-1311 Sequence antisense mUs][fCs][fCs][fG][fG][mU][fU][mA] strand [mU][fA][mA][mC][mU][fG][mA][mA] [mA][mU][mC][mCs][mGs][mG] NR1H3-1220 Artificial Modified [MePhosphonate-4O- 1057 Sequence antisense mUs][fGs][fUs][fC][fU][mU][fC][mC] strand [mC][fG][mG][mU][mU][fA][mU][mA] [mA][mC][mU][mGs][mGs][mG] NR1H3-1221- Artificial Modified [MePhosphonate-4O- 1058 1241-1318 Sequence antisense mUs][fAs][fGs][fU][fC][mU][fU][mC] strand [mC][fC][mG][mG][mU][fU][mA][mU] [mA][mA][mC][mUs][mGs][mG] NR1H3-1224- Artificial Modified [MePhosphonate-4O- 1059 1244 Sequence antisense mUs][fCs][fAs][fA][fA][mG][fU][mC] strand [mU][fU][mC][mC][mC][fG][mG][mU] [mU][mA][mU][mAs][mGs][mG] NR1H3-1244- Artificial Modified [MePhosphonate-4O- 1060 1264 Sequence antisense mUs][fCs][fAs][fC][fU][mU][fG][mC] strand [mA][fG][mC][mC][mC][fU][mG][mC] [mU][mU][mU][mGs][mGs][mG] NR1H3-1249- Artificial Modified [MePhosphonate-4O- 1061 1269-1346 Sequence antisense mUs][fAs][fAs][fU][fU][mC][fC][mA] strand [mC][fU][mU][mG][mC][fA][mG][mC] [mC][mC][mU][mGs][mGs][mG] NR1H3-1252- Artificial Modified [MePhosphonate-4O- 1062 1272 Sequence antisense mUs][fAs][fUs][fG][fA][mA][fU][mU] strand [mC][fC][mA][mC][mU][fU][mG][mC] [mA][mG][mC][mCs][mGs][mG] NR1H3-1254- Artificial Modified [MePhosphonate-4O- 1063 1274-1351 Sequence antisense mUs][fUs][fGs][fA][fU][mG][fA][mA] strand [mU][fU][mC][mC][mA][fC][mU][mU] [mG][mC][mA][mGs][mGs][mG] NR1H3-1255- Artificial Modified [MePhosphonate-4O- 1064 1275-1352 Sequence antisense mUs][fUs][fUs][fG][fA][mU][fG][mA] strand [mA][fU][mU][mC][mC][fA][mC][mU] [mU][mG][mC][mAs][mGs][mG] NR1H3-1256- Artificial Modified [MePhosphonate-4O- 1065 1276-1353 Sequence antisense mUs][fGs][fUs][fU][fG][mA][fU][mG] strand [mA][fA][mU][mU][mC][fC][mA][mC] [mU][mU][mG][mCs][mGs][mG] NR1H3-1257- Artificial Modified [MePhosphonate-4O- 1066 1277-1354 Sequence antisense mUs][fGs][fGs][fU][fU][mG][fA][mU] strand [mG][fA][mA][mU][mU][fC][mC][mA] [mC][mU][mU][mGs][mGs][mG] NR1H3-1259 Artificial Modified [MePhosphonate-4O- 1067 Sequence antisense mUs][fGs][fGs][fG][fG][mU][fU][mG] strand [mA][fU][mG][mA][mA][fU][mU][mC] [mC][mA][mC][mUs][mGs][mG] NR1H3-1260- Artificial Modified [MePhosphonate-4O- 1068 1280-1357 Sequence antisense mUs][fUs][fGs][fG][fG][mG][fU][mU] strand [mG][fA][mU][mG][mA][fA][mU][mU] [mC][mC][mA][mCs][mGs][mG] NR1H3-1261- Artificial Modified [MePhosphonate-4O- 1069 1281-1358 Sequence antisense mUs][fAs][fUs][fG][fG][mG][fG][mU] strand [mU][fG][mA][mU][mG][fA][mA][mU] [mU][mC][mC][mAs][mGs][mG] NR1H3-1263- Artificial Modified [MePhosphonate-4O- 1070 1283-1360 Sequence antisense mUs][fAs][fGs][fA][fU][mG][fG][mG] strand [mG][fU][mU][mG][mA][fU][mG][mA] [mA][mU][mU][mCs][mGs][mG] NR1H3-1264- Artificial Modified [MePhosphonate-4O- 1071 1284-1361 Sequence antisense mUs][fAs][fAs][fG][fA][mU][fG][mG] strand [mG][fG][mU][mU][mG][fA][mU][mG] [mA][mA][mU][mUs][mGs][mG] NR1H3-1265- Artificial Modified [MePhosphonate-4O- 1072 1285 Sequence antisense mUs][fGs][fAs][fA][fG][mA][fU][mG] strand [mG][fG][mG][mU][mU][fG][mA][mU] [mG][mA][mA][mUs][mGs][mG] NR1H3-1266- Artificial Modified [MePhosphonate-4O- 1073 1286 Sequence antisense mUs][fCs][fGs][fA][fA][mG][fA][mU] strand [mG][fG][mG][mG][mU][fU][mG][mA] [mU][mG][mA][mAs][mGs][mG] NR1H3-1405- Artificial Modified [MePhosphonate-4O- 1074 1471-1502 Sequence antisense mUs][fUs][fCs][fC][fA][mC][fA][mU] strand [mA][fU][mG][mU][mG][fU][mG][mC] [mU][mG][mC][mAs][mGs][mG] NR1H3-1409- Artificial Modified [MePhosphonate-4O- 1075 1475-1506 Sequence antisense mUs][fGs][fGs][fC][fU][mU][fC][mC] strand [mA][fC][mA][mU][mA][fU][mG][mU] [mG][mU][mG][mCs][mGs][mG] NR1H3-1429- Artificial Modified [MePhosphonate-4O- 1076 1495 Sequence antisense mUs][fAs][fUs][fG][fG][mA][fG][mA] strand [mC][fG][mU][mA][mG][fG][mC][mA] [mU][mG][mC][mAs][mGs][mG] NR1H3-1433- Artificial Modified [MePhosphonate-4O- 1077 1499 Sequence antisense mUs][fGs][fUs][fG][fG][mA][fU][mG] strand [mG][fA][mG][mA][mC][fG][mU][mA] [mG][mG][mC][mAs][mGs][mG] NR1H3-1437- Artificial Modified [MePhosphonate-4O- 1078 1503 Sequence antisense mUs][fGs][fAs][fU][fG][mG][fU][mG] strand [mG][fA][mU][mG][mG][fA][mG][mA] [mC][mG][mU][mAs][mGs][mG] NR1H3-1439- Artificial Modified [MePhosphonate-4O- 1079 1505 Sequence antisense mUs][fGs][fGs][fG][fA][mU][fG][mG] strand [mU][fG][mG][mA][mU][fG][mG][mA] [mG][mA][mC][mGs][mGs][mG] NR1H3-1446- Artificial Modified [MePhosphonate-4O- 1080 1512 Sequence antisense mUs][fGs][fGs][fU][fC][mA][fU][mG] strand [mG][fG][mG][mA][mU][fG][mG][mU] [mG][mG][mA][mUs][mGs][mG] NR1H3-1458- Artificial Modified [MePhosphonate-4O- 1081 1524-1555 Sequence antisense mUs][fGs][fGs][fA][fA][mC][fA][mU] strand [mC][fA][mG][mU][mC][fG][mG][mU] [mC][mA][mU][mGs][mGs][mG] NR1H3-1463- Artificial Modified [MePhosphonate-4O- 1082 1529 Sequence antisense mUs][fCs][fCs][fG][fU][mG][fG][mG] strand [mA][fA][mC][mA][mU][fC][mA][mG] [mU][mC][mG][mGs][mGs][mG] NR1H3-1464- Artificial Modified [MePhosphonate-4O- 1083 1530-1561 Sequence antisense mUs][fUs][fCs][fC][fG][mU][fG][mG] strand [mG][fA][mA][mC][mA][fU][mC][mA] [mG][mU][mC][mGs][mGs][mG] NR1H3-1465- Artificial Modified [MePhosphonate-4O- 1084 1531-1562 Sequence antisense mUs][fAs][fUs][fC][fC][mG][fU][mG] strand [mG][fG][mA][mA][mC][fA][mU][mC] [mA][mG][mU][mCs][mGs][mG] NR1H3-1467- Artificial Modified [MePhosphonate-4O- 1085 1533-1564 Sequence antisense mUs][fGs][fCs][fA][fU][mC][fC][mG] strand [mU][fG][mG][mG][mA][fA][mC][mA] [mU][mC][mA][mGs][mGs][mG] NR1H3-1469- Artificial Modified [MePhosphonate-4O- 1086 1535-1566 Sequence antisense mUs][fUs][fA][mG][fC][mA][fU][mC] strand [mC][fG][mU][mG][mG][fG][mA][mA] [mC][mA][mU][mCs][mGs][mG] NR1H3-1470- Artificial Modified [MePhosphonate-4O- 1087 1536-1567 Sequence antisense mUs][fUs][fUs][fA][fG][mC][fA][mU] strand [mC][fC][mG][mU][mG][fG][mG][mA] [mA][mC][mA][mUs][mGs][mG] NR1H3-1475- Artificial Modified [MePhosphonate-4O- 1088 1541 Sequence antisense mUs][fUs][fUs][fU][fC][mA][fU][mU] strand [mA][fG][mC][mA][mU][fC][mC][mG] [mU][mG][mG][mGs][mGs][mG] NR1H3-1479- Artificial Modified [MePhosphonate-4O- 1089 1545 Sequence antisense mUs][fCs][fCs][fA][fG][mU][fU][mU] strand [mC][fA][mU][mU][mA][fG][mC][mA] [mU][mC][mC][mGs][mGs][mG] NR1H3-1480- Artificial Modified [MePhosphonate-4O- 1090 1546-1577 Sequence antisense mUs][fAs][fCs][fC][fA][mG][fU][mU] strand [mU][fC][mA][mU][mU][fA][mG][mC] [mA][mU][mC][mCs][mGs][mG] NR1H3-1481- Artificial Modified [MePhosphonate-4O- 1091 1547 Sequence antisense mUs][fCs][fAs][fC][fC][mA][fG][mU] strand [mU][fU][mC][mA][mU][fU][mA][mG] [mC][mA][mU][mCs][mGs][mG] NR1H3-1482- Artificial Modified [MePhosphonate-4O- 1092 1548-1579 Sequence antisense mUs][fUs][fCs][fA][fC][mC][fA][mG] strand [mU][fU][mU][mC][mA][fU][mU][mA] [mG][mC][mA][mUs][mGs][mG] NR1H3-1485- Artificial Modified [MePhosphonate-4O- 1093 1551 Sequence antisense mUs][fGs][fGs][fC][fU][mC][fA][mC] strand [mC][fA][mG][mU][mU][fU][mC][mA] [mU][mU][mA][mGs][mGs][mG] NR1H3-1515- Artificial Modified [MePhosphonate-4O- 1094 1581 Sequence antisense mUs][fGs][fCs][fU][fC][mU][fG][mA] strand [mG][fU][mG][mG][mA][fC][mG][mC] [mU][mG][mC][mUs][mGs][mG] NR1H3-1517- Artificial Modified [MePhosphonate-4O- 1095 1583 Sequence antisense mUs][fUs][fUs][fG][fC][mU][fC][mU] strand [mG][fA][mG][mU][mG][fG][mA][mC] [mG][mC][mU][mGs][mGs][mG] NR1H3-1518- Artificial Modified [MePhosphonate-4O- 1096 1584 Sequence antisense mUs][fCs][fUs][fU][fG][mC][fU][mC] strand [mU][fG][mA][mG][mU][fG][mG][mA] [mC][mG][mC][mUs][mGs][mG] NR1H3-1524- Artificial Modified [MePhosphonate-4O- 1097 1590-1621 Sequence antisense mUs][fCs][fAs][fA][fA][mC][fA][mC] strand [mU][fU][mG][mC][mU][fC][mU][mG] [mA][mG][mU][mGs][mGs][mG] NR1H3-1533- Artificial Modified [MePhosphonate-4O- 1098 1599 Sequence antisense mUs][fGs][fAs][fC][fG][mC][fA][mG] strand [mU][fG][mC][mA][mA][fA][mC][mA] [mC][mU][mU][mGs][mGs][mG] NR1H3-1535- Artificial Modified [MePhosphonate-4O- 1099 1601 Sequence antisense mUs][fCs][fAs][fG][fA][mC][fG][mC] strand [mA][fG][mU][mG][mC][fA][mA][mA] [mC][mA][mC][mUs][mGs][mG] NR1H3-1545- Artificial Modified [MePhosphonate-4O- 1100 1611 Sequence antisense mUs][fUs][fUs][fU][fU][mG][fU][mC] strand [mC][fU][mG][mC][mA][fG][mA][mC] [mG][mC][mA][mGs][mGs][mG] NR1H3-1554- Artificial Modified [MePhosphonate-4O- 1101 1620 Sequence antisense mUs][fGs][fUs][fG][fG][mG][fA][mG] strand [mC][fU][mU][mU][mU][fU][mG][mU] [mC][mC][mU][mGs][mGs][mG] NR1H3-1581- Artificial Modified [MePhosphonate-4O- 1102 1647 Sequence antisense mUs][fGs][fCs][fA][fC][mA][fU][mC] strand [mC][fC][mA][mG][mA][fU][mC][mU] [mC][mA][mG][mAs][mGs][mG] NR1H3-1586- Artificial Modified [MePhosphonate-4O- 1103 1652 Sequence antisense mUs][fUs][fUs][fC][fG][mU][fG][mC] strand [mA][fC][mA][mU][mC][fC][mC][mA] [mG][mA][mU][mCs][mGs][mG] NR1H3-1587- Artificial Modified [MePhosphonate-4O- 1104 1653 Sequence antisense mUs][fAs][fUs][fU][fC][mG][fU][mG] strand [mC][fA][mC][mA][mU][fC][mC][mC] [mA][mG][mA][mUs][mGs][mG] NR1H3-1588- Artificial Modified [MePhosphonate-4O- 1105 1654 Sequence antisense mUs][fCs][fAs][fU][fU][mC][fG][mU] strand [mG][fC][mA][mC][mA][fU][mC][mC] [mC][mA][mG][mAs][mGs][mG] NR1H3-1594- Artificial Modified [MePhosphonate-4O- 1106 1660-1691 Sequence antisense mUs][fAs][fAs][fC][fA][mG][fU][mC] strand [mA][fU][mU][mC][mG][fU][mG][mC] [mA][mC][mA][mUs][mGs][mG] NR1H3-1595- Artificial Modified [MePhosphonate-4O- 1107 1661-1692 Sequence antisense mUs][fGs][fAs][fA][fC][mA][fG][mU] strand [mC][fA][mU][mU][mC][fG][mU][mG] [mC][mA][mC][mAs][mGs][mG] NR1H3-1596- Artificial Modified [MePhosphonate-4O- 1108 1662 Sequence antisense mUs][fAs][fGs][fA][fA][mC][fA][mG] strand [mU][fC][mA][mU][mU][fC][mG][mU] [mG][mC][mA][mCs][mGs][mG] NR1H3-1663- Artificial Modified [MePhosphonate-4O- 1109 1727 Sequence antisense mUs][fGs][fUs][fU][fC][mC][fA][mC] strand [mU][fU][mC][mU][mA][fG][mG][mA] [mG][mG][mC][mAs][mGs][mG] NR1H3-1670- Artificial Modified [MePhosphonate-4O- 1110 1734 Sequence antisense mUs][fUs][fCs][fA][fG][mU][fC][mU] strand [mG][fU][mU][mC][mC][fA][mC][mU] [mU][mC][mU][mAs][mGs][mG] NR1H3-1671- Artificial Modified [MePhosphonate-4O- 1111 1735 Sequence antisense mUs][fCs][fUs][fC][fA][mG][fU][mC] strand [mU][fG][mU][mU][mC][fC][mA][mC] [mU][mU][mC][mUs][mGs][mG] NR1H3-1672- Artificial Modified [MePhosphonate-4O- 1112 1736 Sequence antisense mUs][fUs][fCs][fU][fC][mA][fG][mU] strand [mC][fU][mG][mU][mU][fC][mC][mA] [mC][mU][mU][mCs][mGs][mG] NR1H3-1673- Artificial Modified [MePhosphonate-4O- 1113 1737 Sequence antisense mUs][fUs][fUs][fC][fU][mC][fA][mG] strand [mU][fC][mU][mG][mU][fU][mC][mC] [mA][mC][mU][mUs][mGs][mG] NR1H3-1674- Artificial Modified [MePhosphonate-4O- 1114 1738 Sequence antisense mUs][fCs][fUs][fU][fC][mU][fC][mA] strand [mG][fU][mC][mU][mG][fU][mU][mC] [mC][mA][mC][mUs][mGs][mG] NR1H3-1675- Artificial Modified [MePhosphonate-4O- 1115 1739-1766 Sequence antisense mUs][fCs][fCs][fU][fU][mC][fU][mC] strand [mA][fG][mU][mC][mU][fG][mU][mU] [mC][mC][mA][mCs][mGs][mG] NR1H3-1676- Artificial Modified [MePhosphonate-4O- 1116 1740-1767 Sequence antisense mUs][fCs][fCs][fC][fU][mU][fC][mU] strand [mC][fA][mG][mU][mC][fU][mG][mU] [mU][mC][mC][mAs][mGs][mG] NR1H3-1678- Artificial Modified [MePhosphonate-4O- 1117 1742-1769 Sequence antisense mUs][fUs][fGs][fC][fC][mC][fU][mU] strand [mC][fU][mC][mA][mG][fU][mC][mU] [mG][mU][mU][mCs][mGs][mG] NR1H3-1684- Artificial Modified [MePhosphonate-4O- 1118 1748 Sequence antisense mUs][fAs][fAs][fU][fG][mU][fU][mU] strand [mG][fC][mC][mC][mU][fU][mC][mU] [mC][mA][mG][mUs][mGs][mG] NR1H3-1731- Artificial Modified [MePhosphonate-4O- 1119 1795 Sequence antisense mUs][fGs][fAs][fC][fU][mC][fU][mC] strand [mU][fU][mU][mU][mA][fA][mU][mG] [mC][mC][mA][mCs][mGs][mG] NR1H3-1732- Artificial Modified [MePhosphonate-4O- 1120 1796 Sequence antisense mUs][fUs][fGs][fA][fC][mU][fC][mU] strand [mC][fU][mU][mU][mU][fA][mA][mU] [mG][mC][mC][mAs][mGs][mG] Stem-loop Artificial GCAGCCGAAAGGCUGC 1121 Sequence Forward-1198 Artificial GTTATAACCGGGAAGACTTTGC 1122 Sequence Reverse-1326 Artificial TGATAGCAATGAGCAAGGCA 1123 Sequence Probe-1253 Artificial ATGGCCCTGGAGAACTCGAAGAT 1124 Sequence G NR1H3-764- Hs-Mf- 19 mer sense UGUCCUGUCAGAAGAACAG 1125 784-861 Mm strand NR1H3-766- Hs-Mf- 19 mer sense UCCUGUCAGAAGAACAGAU 1126 786-863 Mm strand NR1H3-789- Hs-Mf- 19 mer sense CUGAAGAAACUGAAGCGGC 1127 809-886 Mm strand NR1H3-790- Hs-Mf- 19 mer sense UGAAGAAACUGAAGCGGCA 1128 810-887 Mm strand NR1H3-791- Hs-Mf- 19 mer sense GAAGAAACUGAAGCGGCAA 1129 811-888 Mm strand NR1H3-792- Hs-Mf- 19 mer sense AAGAAACUGAAGCGGCAAG 1130 812-889 Mm strand NR1H3-793- Hs-Mf- 19 mer sense AGAAACUGAAGCGGCAAGA 1131 813-890 Mm strand NR1H3-795- Hs-Mf- 19 mer sense AAACUGAAGCGGCAAGAGG 1132 815-892 Mm strand NR1H3-796- Hs-Mf- 19 mer sense AACUGAAGCGGCAAGAGGA 1133 816-893 Mm strand NR1H3-797- Hs-Mf- 19 mer sense ACUGAAGCGGCAAGAGGAG 1134 817-894 Mm strand NR1H3-798- Hs-Mf- 19 mer sense CUGAAGCGGCAAGAGGAGG 1135 818-895 Mm strand NR1H3-799- Hs-Mf- 19 mer sense UGAAGCGGCAAGAGGAGGA 1136 819-896 Mm strand NR1H3-802- Hs-Mf- 19 mer sense AGCGGCAAGAGGAGGAACA 1137 822-899 Mm strand NR1H3-803- Hs-Mf- 19 mer sense GCGGCAAGAGGAGGAACAG 1138 823-900 Mm strand NR1H3-804- Hs-Mf- 19 mer sense CGGCAAGAGGAGGAACAGG 1139 824-901 Mm strand NR1H3-806- Hs-Mf- 19 mer sense GCAAGAGGAGGAACAGGCU 1140 826-903 Mm strand NR1H3-808- Hs-Mf- 19 mer sense AAGAGGAGGAACAGGCUCA 1141 828-905 Mm strand NR1H3-809- Hs-Mf- 19 mer sense AGAGGAGGAACAGGCUCAU 1142 829-906 Mm strand NR1H3-810- Hs-Mf- 19 mer sense GAGGAGGAACAGGCUCAUG 1143 830-907 Mm strand NR1H3-811- Hs-Mf- 19 mer sense AGGAGGAACAGGCUCAUGC 1144 831-908 Mm strand NR1H3-813- Hs-Mf- 19 mer sense GAGGAACAGGCUCAUGCCA 1145 833-910 Mm strand NR1H3-844- Hs-Mf 19 mer sense CCAGGGCUUCCUCACCCCC 1146 864 strand NR1H3-895- Hs-Mf- 19 mer sense UGGGCAUGAUCGAGAAGCU 1147 915-992 Mm strand NR1H3-898- Hs-Mf- 19 mer sense GCAUGAUCGAGAAGCUCGU 1148 918-995 Mm strand NR1H3-915- Hs-Mf- 19 mer sense GUCGCUGCCCAGCAACAGU 1149 935-1012 Mm strand NR1H3-917- Hs-Mf- 19 mer sense CGCUGCCCAGCAACAGUGU 1150 937-1014 Mm strand NR1H3-922- Hs-Mf- 19 mer sense CCCAGCAACAGUGUAACCG 1151 942-1019 Mm strand NR1H3-924- Hs-Mf- 19 mer sense CAGCAACAGUGUAACCGGC 1152 944-1021 Mm strand NR1H3-925- Hs-Mf- 19 mer sense AGCAACAGUGUAACCGGCG 1153 945-1022 Mm strand NR1H3-927- Hs-Mf- 19 mer sense CAACAGUGUAACCGGCGCU 1154 947-1024 Mm strand NR1H3-928- Hs-Mf- 19 mer sense AACAGUGUAACCGGCGCUC 1155 948-1025 Mm strand NR1H3-929- Hs-Mf- 19 mer sense ACAGUGUAACCGGCGCUCC 1156 949-1026 Mm strand NR1H3-930- Hs-Mf- 19 mer sense CAGUGUAACCGGCGCUCCU 1157 950-1027 Mm strand NR1H3-931- Hs-Mf- 19 mer sense AGUGUAACCGGCGCUCCUU 1158 951-1028 Mm strand NR1H3-932- Hs-Mf- 19 mer sense GUGUAACCGGCGCUCCUUU 1159 952-1029 Mm strand NR1H3-933- Hs-Mf- 19 mer sense UGUAACCGGCGCUCCUUUU 1160 953-1030 Mm strand NR1H3-941- Hs-Mf 19 mer sense GCGCUCCUUUUCUGACCGG 1161 961 strand NR1H3-944- Hs-Mf 19 mer sense CUCCUUUUCUGACCGGCUU 1162 964 strand NR1H3-945- Hs-Mf 19 mer sense UCCUUUUCUGACCGGCUUC 1163 965 strand NR1H3-946- Hs-Mf 19 mer sense CCUUUUCUGACCGGCUUCG 1164 966 strand NR1H3-947- Hs-Mf 19 mer sense CUUUUCUGACCGGCUUCGA 1165 967 strand NR1H3-949- Hs-Mf 19 mer sense UUUCUGACCGGCUUCGAGU 1166 969 strand NR1H3-951- Hs-Mf 19 mer sense UCUGACCGGCUUCGAGUCA 1167 971 strand NR1H3-952- Hs-Mf 19 mer sense CUGACCGGCUUCGAGUCAC 1168 972 strand NR1H3-953- Hs-Mf 19 mer sense UGACCGGCUUCGAGUCACG 1169 973 strand NR1H3-1151- Hs-Mf- 19 mer sense GGUGAUGCUUCUGGAGACA 1170 1171-1248 Mm strand NR1H3-1153- Hs-Mf- 19 mer sense UGAUGCUUCUGGAGACAUC 1171 1173-1250 Mm strand NR1H3-1154- Hs-Mf- 19 mer sense GAUGCUUCUGGAGACAUCU 1172 1174-1251 Mm strand NR1H3-1155- Hs-Mf- 19 mer sense AUGCUUCUGGAGACAUCUC 1173 1175-1252 Mm strand NR1H3-1156- Hs-Mf- 19 mer sense UGCUUCUGGAGACAUCUCG 1174 1176-1253 Mm strand NR1H3-1157- Hs-Mf- 19 mer sense GCUUCUGGAGACAUCUCGG 1175 1177-1254 Mm strand NR1H3-1158- Hs-Mf- 19 mer sense CUUCUGGAGACAUCUCGGA 1176 1178-1255 Mm strand NR1H3-1159- Hs-Mf- 19 mer sense UUCUGGAGACAUCUCGGAG 1177 1179-1256 Mm strand NR1H3-1160- Hs-Mf- 19 mer sense UCUGGAGACAUCUCGGAGG 1178 1180-1257 Mm strand NR1H3-1161- Hs-Mf- 19 mer sense CUGGAGACAUCUCGGAGGU 1179 1181-1258 Mm strand NR1H3-1162- Hs-Mf- 19 mer sense UGGAGACAUCUCGGAGGUA 1180 1182-1259 Mm strand NR1H3-1163- Hs-Mf- 19 mer sense GGAGACAUCUCGGAGGUAC 1181 1183-1260 Mm strand NR1H3-1164- Hs-Mf- 19 mer sense GAGACAUCUCGGAGGUACA 1182 1184-1261 Mm strand NR1H3-1165- Hs-Mf- 19 mer sense AGACAUCUCGGAGGUACAA 1183 1185-1262 Mm strand NR1H3-1166- Hs-Mf- 19 mer sense GACAUCUCGGAGGUACAAC 1184 1186-1263 Mm strand NR1H3-1167- Hs-Mf- 19 mer sense ACAUCUCGGAGGUACAACC 1185 1187-1264 Mm strand NR1H3-1169- Hs-Mf- 19 mer sense AUCUCGGAGGUACAACCCU 1186 1189-1266 Mm strand NR1H3-1170- Hs-Mf- 19 mer sense UCUCGGAGGUACAACCCUG 1187 1190-1267 Mm strand NR1H3-1171- Hs-Mf- 19 mer sense CUCGGAGGUACAACCCUGG 1188 1191-1268 Mm strand NR1H3-1173- Hs-Mf- 19 mer sense CGGAGGUACAACCCUGGGA 1189 1193-1270 Mm strand NR1H3-1175- Hs-Mf- 19 mer sense GAGGUACAACCCUGGGAGU 1190 1195-1272 Mm strand NR1H3-1176- Hs-Mf- 19 mer sense AGGUACAACCCUGGGAGUG 1191 1196-1273 Mm strand NR1H3-1177- Hs-Mf- 19 mer sense GGUACAACCCUGGGAGUGA 1192 1197-1274 Mm strand NR1H3-1178- Hs-Mf- 19 mer sense GUACAACCCUGGGAGUGAG 1193 1198-1275 Mm strand NR1H3-1179- Hs-Mf- 19 mer sense UACAACCCUGGGAGUGAGA 1194 1199-1276 Mm strand NR1H3-1180- Hs-Mf- 19 mer sense ACAACCCUGGGAGUGAGAG 1195 1200-1277 Mm strand NR1H3-1181- Hs-Mf- 19 mer sense CAACCCUGGGAGUGAGAGU 1196 1201-1278 Mm strand NR1H3-1182- Hs-Mf- 19 mer sense AACCCUGGGAGUGAGAGUA 1197 1202-1279 Mm strand NR1H3-1183- Hs-Mf- 19 mer sense ACCCUGGGAGUGAGAGUAU 1198 1203-1280 Mm strand NR1H3-1184- Hs-Mf- 19 mer sense CCCUGGGAGUGAGAGUAUC 1199 1204-1281 Mm strand NR1H3-1185- Hs-Mf- 19 mer sense CCUGGGAGUGAGAGUAUCA 1200 1205-1282 Mm strand NR1H3-1186- Hs-Mf- 19 mer sense CUGGGAGUGAGAGUAUCAC 1201 1206-1283 Mm strand NR1H3-1187- Hs-Mf- 19 mer sense UGGGAGUGAGAGUAUCACC 1202 1207-1284 Mm strand NR1H3-1188- Hs-Mf- 19 mer sense GGGAGUGAGAGUAUCACCU 1203 1208-1285 Mm strand NR1H3-1190- Hs-Mf- 19 mer sense GAGUGAGAGUAUCACCUUC 1204 1210-1287 Mm strand NR1H3-1191- Hs-Mf- 19 mer sense AGUGAGAGUAUCACCUUCC 1205 1211-1288 Mm strand NR1H3-1192- Hs-Mf- 19 mer sense GUGAGAGUAUCACCUUCCU 1206 1212-1289 Mm strand NR1H3-1193- Hs-Mf- 19 mer sense UGAGAGUAUCACCUUCCUC 1207 1213-1290 Mm strand NR1H3-1194- Hs-Mf- 19 mer sense GAGAGUAUCACCUUCCUCA 1208 1214-1291 Mm strand NR1H3-1196- Hs-Mf- 19 mer sense GAGUAUCACCUUCCUCAAG 1209 1216-1293 Mm strand NR1H3-1197- Hs-Mf- 19 mer sense AGUAUCACCUUCCUCAAGG 1210 1217-1294 Mm strand NR1H3-1198- Hs-Mf- 19 mer sense GUAUCACCUUCCUCAAGGA 1211 1218-1295 Mm strand NR1H3-1199- Hs-Mf- 19 mer sense UAUCACCUUCCUCAAGGAU 1212 1219-1296 Mm strand NR1H3-1200- Hs-Mf- 19 mer sense AUCACCUUCCUCAAGGAUU 1213 1220-1297 Mm strand NR1H3-1203- Hs-Mf- 19 mer sense ACCUUCCUCAAGGAUUUCA 1214 1223-1300 Mm strand NR1H3-1204- Hs-Mf- 19 mer sense CCUUCCUCAAGGAUUUCAG 1215 1224-1301 Mm strand NR1H3-1207- Hs-Mf- 19 mer sense UCCUCAAGGAUUUCAGUUA 1216 1227-1304 Mm strand NR1H3-1211- Hs-Mf- 19 mer sense CAAGGAUUUCAGUUAUAAC 1217 1231-1308 Mm strand NR1H3-1212- Hs-Mf- 19 mer sense AAGGAUUUCAGUUAUAACC 1218 1232-1309 Mm strand NR1H3-1213- Hs-Mf- 19 mer sense AGGAUUUCAGUUAUAACCG 1219 1233-1310 Mm strand NR1H3-1214- Hs-Mf- 19 mer sense GGAUUUCAGUUAUAACCGG 1220 1234-1311 Mm strand NR1H3-1215- Hs-Mf- 19 mer sense GAUUUCAGUUAUAACCGGG 1221 1235-1312 Mm strand NR1H3-1216- Hs-Mf- 19 mer sense AUUUCAGUUAUAACCGGGA 1222 1236-1313 Mm strand NR1H3-1217- Hs-Mf- 19 mer sense UUUCAGUUAUAACCGGGAA 1223 1237-1314 Mm strand NR1H3-1218- Hs-Mf- 19 mer sense UUCAGUUAUAACCGGGAAG 1224 1238-1315 Mm strand NR1H3-1219- Hs-Mf- 19 mer sense UCAGUUAUAACCGGGAAGA 1225 1239-1316 Mm strand NR1H3-1220- Hs-Mf- 19 mer sense CAGUUAUAACCGGGAAGAC 1226 1240-1317 Mm strand NR1H3-1222- Hs-Mf- 19 mer sense GUUAUAACCGGGAAGACUU 1227 1242-1319 Mm strand NR1H3-1223- Hs-Mf- 19 mer sense UUAUAACCGGGAAGACUUU 1228 1243-1320 Mm strand NR1H3-1224- Hs-Mf- 19 mer sense UAUAACCGGGAAGACUUUG 1229 1244-1321 Mm strand NR1H3-1225- Hs-Mf- 19 mer sense AUAACCGGGAAGACUUUGC 1230 1245-1322 Mm strand NR1H3-1226- Hs-Mf- 19 mer sense UAACCGGGAAGACUUUGCC 1231 1246-1323 Mm strand NR1H3-1227- Hs-Mf- 19 mer sense AACCGGGAAGACUUUGCCA 1232 1247-1324 Mm strand NR1H3-1228- Hs-Mf- 19 mer sense ACCGGGAAGACUUUGCCAA 1233 1248-1325 Mm strand NR1H3-1229- Hs-Mf- 19 mer sense CCGGGAAGACUUUGCCAAA 1234 1249-1326 Mm strand NR1H3-1232- Hs-Mf- 19 mer sense GGAAGACUUUGCCAAAGCA 1235 1252-1329 Mm strand NR1H3-1233- Hs-Mf- 19 mer sense GAAGACUUUGCCAAAGCAG 1236 1253-1330 Mm strand NR1H3-1234- Hs-Mf- 19 mer sense AAGACUUUGCCAAAGCAGG 1237 1254-1331 Mm strand NR1H3-1235- Hs-Mf- 19 mer sense AGACUUUGCCAAAGCAGGG 1238 1255-1332 Mm strand NR1H3-1236- Hs-Mf- 19 mer sense GACUUUGCCAAAGCAGGGC 1239 1256-1333 Mm strand NR1H3-1237- Hs-Mf- 19 mer sense ACUUUGCCAAAGCAGGGCU 1240 1257-1334 Mm strand NR1H3-1238- Hs-Mf- 19 mer sense CUUUGCCAAAGCAGGGCUG 1241 1258-1335 Mm strand NR1H3-1241- Hs-Mf- 19 mer sense UGCCAAAGCAGGGCUGCAA 1242 1261-1338 Mm strand NR1H3-1242- Hs-Mf- 19 mer sense GCCAAAGCAGGGCUGCAAG 1243 1262-1339 Mm strand NR1H3-1243- Hs-Mf- 19 mer sense CCAAAGCAGGGCUGCAAGU 1244 1263-1340 Mm strand NR1H3-1244- Hs-Mf- 19 mer sense CAAAGCAGGGCUGCAAGUG 1245 1264-1341 Mm strand NR1H3-1245- Hs-Mf- 19 mer sense AAAGCAGGGCUGCAAGUGG 1246 1265-1342 Mm strand NR1H3-1246- Hs-Mf- 19 mer sense AAGCAGGGCUGCAAGUGGA 1247 1266-1343 Mm strand NR1H3-1247- Hs-Mf- 19 mer sense AGCAGGGCUGCAAGUGGAA 1248 1267-1344 Mm strand NR1H3-1248- Hs-Mf- 19 mer sense GCAGGGCUGCAAGUGGAAU 1249 1268-1345 Mm strand NR1H3-1250- Hs-Mf- 19 mer sense AGGGCUGCAAGUGGAAUUC 1250 1270-1347 Mm strand NR1H3-1251- Hs-Mf- 19 mer sense GGGCUGCAAGUGGAAUUCA 1251 1271-1348 Mm strand NR1H3-1252- Hs-Mf- 19 mer sense GGCUGCAAGUGGAAUUCAU 1252 1272-1349 Mm strand NR1H3-1253- Hs-Mf- 19 mer sense GCUGCAAGUGGAAUUCAUC 1253 1273-1350 Mm strand NR1H3-1256- Hs-Mf- 19 mer sense GCAAGUGGAAUUCAUCAAC 1254 1276-1353 Mm strand NR1H3-1258- Hs-Mf- 19 mer sense AAGUGGAAUUCAUCAACCC 1255 1278-1355 Mm strand NR1H3-1259- Hs-Mf- 19 mer sense AGUGGAAUUCAUCAACCCC 1256 1279-1356 Mm strand NR1H3-1261- Hs-Mf- 19 mer sense UGGAAUUCAUCAACCCCAU 1257 1281-1358 Mm strand NR1H3-1262- Hs-Mf- 19 mer sense GGAAUUCAUCAACCCCAUC 1258 1282-1359 Mm strand NR1H3-1265- Hs-Mf- 19 mer sense AUUCAUCAACCCCAUCUUC 1259 1285-1362 Mm strand NR1H3-1266- Hs-Mf- 19 mer sense UUCAUCAACCCCAUCUUCG 1260 1286-1363 Mm strand NR1H3-1267- Hs-Mf- 19 mer sense UCAUCAACCCCAUCUUCGA 1261 1287-1364 Mm strand NR1H3-1268- Hs-Mf- 19 mer sense CAUCAACCCCAUCUUCGAG 1262 1288-1365 Mm strand NR1H3-1269- Hs-Mf- 19 mer sense AUCAACCCCAUCUUCGAGU 1263 1289-1366 Mm strand NR1H3-1270- Hs-Mf- 19 mer sense UCAACCCCAUCUUCGAGUU 1264 1290-1367 Mm strand NR1H3-1271- Hs-Mf- 19 mer sense CAACCCCAUCUUCGAGUUC 1265 1291-1368 Mm strand NR1H3-1272- Hs-Mf- 19 mer sense AACCCCAUCUUCGAGUUCU 1266 1292-1369 Mm strand NR1H3-1273- Hs-Mf- 19 mer sense ACCCCAUCUUCGAGUUCUC 1267 1293-1370 Mm strand NR1H3-1275- Hs-Mf- 19 mer sense CCCAUCUUCGAGUUCUCCA 1268 1295-1372 Mm strand NR1H3-1276- Hs-Mf- 19 mer sense CCAUCUUCGAGUUCUCCAG 1269 1296-1373 Mm strand NR1H3-1277- Hs-Mf- 19 mer sense CAUCUUCGAGUUCUCCAGG 1270 1297-1374 Mm strand NR1H3-1278- Hs-Mf- 19 mer sense AUCUUCGAGUUCUCCAGGG 1271 1298-1375 Mm strand NR1H3-1279- Hs-Mf- 19 mer sense UCUUCGAGUUCUCCAGGGC 1272 1299-1376 Mm strand NR1H3-1280- Hs-Mf- 19 mer sense CUUCGAGUUCUCCAGGGCC 1273 1300-1377 Mm strand NR1H3-1281- Hs-Mf- 19 mer sense UUCGAGUUCUCCAGGGCCA 1274 1301-1378 Mm strand NR1H3-1282- Hs-Mf- 19 mer sense UCGAGUUCUCCAGGGCCAU 1275 1302-1379 Mm strand NR1H3-1283- Hs-Mf- 19 mer sense CGAGUUCUCCAGGGCCAUG 1276 1303-1380 Mm strand NR1H3-1284- Hs-Mf- 19 mer sense GAGUUCUCCAGGGCCAUGA 1277 1304-1381 Mm strand NR1H3-1285- Hs-Mf- 19 mer sense AGUUCUCCAGGGCCAUGAA 1278 1305-1382 Mm strand NR1H3-1286- Hs-Mf- 19 mer sense GUUCUCCAGGGCCAUGAAU 1279 1306-1383 Mm strand NR1H3-1288- Hs-Mf- 19 mer sense UCUCCAGGGCCAUGAAUGA 1280 1308-1385 Mm strand NR1H3-1289- Hs-Mf- 19 mer sense CUCCAGGGCCAUGAAUGAG 1281 1309-1386 Mm strand NR1H3-1290- Hs-Mf- 19 mer sense UCCAGGGCCAUGAAUGAGC 1282 1310-1387 Mm strand NR1H3-1291- Hs-Mf- 19 mer sense CCAGGGCCAUGAAUGAGCU 1283 1311-1388 Mm strand NR1H3-1292- Hs-Mf- 19 mer sense CAGGGCCAUGAAUGAGCUG 1284 1312-1389 Mm strand NR1H3-1293- Hs-Mf- 19 mer sense AGGGCCAUGAAUGAGCUGC 1285 1313-1390 Mm strand NR1H3-1294- Hs-Mf- 19 mer sense GGGCCAUGAAUGAGCUGCA 1286 1314-1391 Mm strand NR1H3-1295- Hs-Mf- 19 mer sense GGCCAUGAAUGAGCUGCAA 1287 1315-1392 Mm strand NR1H3-1296- Hs-Mf- 19 mer sense GCCAUGAAUGAGCUGCAAC 1288 1316-1393 Mm strand NR1H3-1297- Hs-Mf- 19 mer sense CCAUGAAUGAGCUGCAACU 1289 1317-1394 Mm strand NR1H3-1338- Hs-Mf- 19 mer sense CUCAUUGCUAUCAGCAUCU 1290 1358-1435 Mm strand NR1H3-1339- Hs-Mf- 19 mer sense UCAUUGCUAUCAGCAUCUU 1291 1359-1436 Mm strand NR1H3-1340- Hs-Mf- 19 mer sense CAUUGCUAUCAGCAUCUUC 1292 1360-1437 Mm strand NR1H3-1341- Hs-Mf- 19 mer sense AUUGCUAUCAGCAUCUUCU 1293 1361-1438 Mm strand NR1H3-1342- Hs-Mf- 19 mer sense UUGCUAUCAGCAUCUUCUC 1294 1362-1439 Mm strand NR1H3-1343- Hs-Mf- 19 mer sense UGCUAUCAGCAUCUUCUCU 1295 1363-1440 Mm strand NR1H3-1344- Hs-Mf- 19 mer sense GCUAUCAGCAUCUUCUCUG 1296 1364-1441 Mm strand NR1H3-1345- Hs-Mf- 19 mer sense CUAUCAGCAUCUUCUCUGC 1297 1365-1442 Mm strand NR1H3-1346- Hs-Mf- 19 mer sense UAUCAGCAUCUUCUCUGCA 1298 1366-1443 Mm strand NR1H3-1347- Hs-Mf- 19 mer sense AUCAGCAUCUUCUCUGCAG 1299 1367-1444 Mm strand NR1H3-1377- Hs-Mf- 19 mer sense GUGCAGGACCAGCUCCAGG 1300 1443-1474 Mm strand NR1H3-1379- Hs-Mf- 19 mer sense GCAGGACCAGCUCCAGGUA 1301 1445-1476 Mm strand NR1H3-1383- Hs-Mf- 19 mer sense GACCAGCUCCAGGUAGAGA 1302 1449-1480 Mm strand NR1H3-1384- Hs-Mf- 19 mer sense ACCAGCUCCAGGUAGAGAG 1303 1450-1481 Mm strand NR1H3-1385- Hs-Mf- 19 mer sense CCAGCUCCAGGUAGAGAGG 1304 1451-1482 Mm strand NR1H3-1387- Hs-Mf- 19 mer sense AGCUCCAGGUAGAGAGGCU 1305 1453-1484 Mm strand NR1H3-1388- Hs-Mf- 19 mer sense GCUCCAGGUAGAGAGGCUG 1306 1454-1485 Mm strand NR1H3-1391- Hs-Mf- 19 mer sense CCAGGUAGAGAGGCUGCAG 1307 1457-1488 Mm strand NR1H3-1393- Hs-Mf- 19 mer sense AGGUAGAGAGGCUGCAGCA 1308 1459-1490 Mm strand NR1H3-1394- Hs-Mf- 19 mer sense GGUAGAGAGGCUGCAGCAC 1309 1460-1491 Mm strand NR1H3-1395- Hs-Mf- 19 mer sense GUAGAGAGGCUGCAGCACA 1310 1461-1492 Mm strand NR1H3-1396- Hs-Mf- 19 mer sense UAGAGAGGCUGCAGCACAC 1311 1462-1493 Mm strand NR1H3-1397- Hs-Mf- 19 mer sense AGAGAGGCUGCAGCACACA 1312 1463-1494 Mm strand NR1H3-1398- Hs-Mf- 19 mer sense GAGAGGCUGCAGCACACAU 1313 1464-1495 Mm strand NR1H3-1399- Hs-Mf- 19 mer sense AGAGGCUGCAGCACACAUA 1314 1465-1496 Mm strand NR1H3-1400- Hs-Mf- 19 mer sense GAGGCUGCAGCACACAUAU 1315 1466-1497 Mm strand NR1H3-1401- Hs-Mf- 19 mer sense AGGCUGCAGCACACAUAUG 1316 1467-1498 Mm strand NR1H3-1402- Hs-Mf- 19 mer sense GGCUGCAGCACACAUAUGU 1317 1468-1499 Mm strand NR1H3-1403- Hs-Mf- 19 mer sense GCUGCAGCACACAUAUGUG 1318 1469-1500 Mm strand NR1H3-1404- Hs-Mf- 19 mer sense CUGCAGCACACAUAUGUGG 1319 1470-1501 Mm strand NR1H3-1406- Hs-Mf- 19 mer sense GCAGCACACAUAUGUGGAA 1320 1472-1503 Mm strand NR1H3-1407- Hs-Mf- 19 mer sense CAGCACACAUAUGUGGAAG 1321 1473-1504 Mm strand NR1H3-1408- Hs-Mf- 19 mer sense AGCACACAUAUGUGGAAGC 1322 1474-1505 Mm strand NR1H3-1410- Hs-Mf- 19 mer sense CACACAUAUGUGGAAGCCC 1323 1476-1507 Mm strand NR1H3-1411- Hs-Mf- 19 mer sense ACACAUAUGUGGAAGCCCU 1324 1477-1508 Mm strand NR1H3-1412- Hs-Mf- 19 mer sense CACAUAUGUGGAAGCCCUG 1325 1478-1509 Mm strand NR1H3-1413- Hs-Mf- 19 mer sense ACAUAUGUGGAAGCCCUGC 1326 1479-1510 Mm strand NR1H3-1414- Hs-Mf- 19 mer sense CAUAUGUGGAAGCCCUGCA 1327 1480-1511 Mm strand NR1H3-1415- Hs-Mf- 19 mer sense AUAUGUGGAAGCCCUGCAU 1328 1481-1512 Mm strand NR1H3-1416- Hs-Mf- 19 mer sense UAUGUGGAAGCCCUGCAUG 1329 1482-1513 Mm strand NR1H3-1417- Hs-Mf- 19 mer sense AUGUGGAAGCCCUGCAUGC 1330 1483-1514 Mm strand NR1H3-1418- Hs-Mf- 19 mer sense UGUGGAAGCCCUGCAUGCC 1331 1484-1515 Mm strand NR1H3-1419- Hs-Mf- 19 mer sense GUGGAAGCCCUGCAUGCCU 1332 1485-1516 Mm strand NR1H3-1420- Hs-Mf- 19 mer sense UGGAAGCCCUGCAUGCCUA 1333 1486-1517 Mm strand NR1H3-1421- Hs-Mf- 19 mer sense GGAAGCCCUGCAUGCCUAC 1334 1487-1518 Mm strand NR1H3-1422- Hs-Mf- 19 mer sense GAAGCCCUGCAUGCCUACG 1335 1488-1519 Mm strand NR1H3-1423- Hs-Mf- 19 mer sense AAGCCCUGCAUGCCUACGU 1336 1489-1520 Mm strand NR1H3-1424- Hs-Mf- 19 mer sense AGCCCUGCAUGCCUACGUC 1337 1490-1521 Mm strand NR1H3-1425- Hs-Mf- 19 mer sense GCCCUGCAUGCCUACGUCU 1338 1491-1522 Mm strand NR1H3-1426- Hs-Mf- 19 mer sense CCCUGCAUGCCUACGUCUC 1339 1492-1523 Mm strand NR1H3-1427- Hs-Mf- 19 mer sense CCUGCAUGCCUACGUCUCC 1340 1493-1524 Mm strand NR1H3-1428- Hs-Mf- 19 mer sense CUGCAUGCCUACGUCUCCA 1341 1494-1525 Mm strand NR1H3-1429- Hs-Mf- 19 mer sense UGCAUGCCUACGUCUCCAU 1342 1495-1526 Mm strand NR1H3-1430- Hs-Mf- 19 mer sense GCAUGCCUACGUCUCCAUC 1343 1496-1527 Mm strand NR1H3-1431- Hs-Mf- 19 mer sense CAUGCCUACGUCUCCAUCC 1344 1497-1528 Mm strand NR1H3-1432- Hs-Mf- 19 mer sense AUGCCUACGUCUCCAUCCA 1345 1498-1529 Mm strand NR1H3-1433- Hs-Mf- 19 mer sense UGCCUACGUCUCCAUCCAC 1346 1499-1530 Mm strand NR1H3-1434- Hs-Mf- 19 mer sense GCCUACGUCUCCAUCCACC 1347 1500-1531 Mm strand NR1H3-1435- Hs-Mf- 19 mer sense CCUACGUCUCCAUCCACCA 1348 1501-1532 Mm strand NR1H3-1436- Hs-Mf- 19 mer sense CUACGUCUCCAUCCACCAU 1349 1502-1533 Mm strand NR1H3-1437- Hs-Mf- 19 mer sense UACGUCUCCAUCCACCAUC 1350 1503-1534 Mm strand NR1H3-1438- Hs-Mf- 19 mer sense ACGUCUCCAUCCACCAUCC 1351 1504-1535 Mm strand NR1H3-1439- Hs-Mf- 19 mer sense CGUCUCCAUCCACCAUCCC 1352 1505-1536 Mm strand NR1H3-1440- Hs-Mf- 19 mer sense GUCUCCAUCCACCAUCCCC 1353 1506-1537 Mm strand NR1H3-1442- Hs-Mf- 19 mer sense CUCCAUCCACCAUCCCCAU 1354 1508-1539 Mm strand NR1H3-1443- Hs-Mf- 19 mer sense UCCAUCCACCAUCCCCAUG 1355 1509-1540 Mm strand NR1H3-1444- Hs-Mf- 19 mer sense CCAUCCACCAUCCCCAUGA 1356 1510-1541 Mm strand NR1H3-1445- Hs-Mf- 19 mer sense CAUCCACCAUCCCCAUGAC 1357 1511-1542 Mm strand NR1H3-1446- Hs-Mf- 19 mer sense AUCCACCAUCCCCAUGACC 1358 1512-1543 Mm strand NR1H3-1447- Hs-Mf 19 mer sense UCCACCAUCCCCAUGACCG 1359 1513 strand NR1H3-1448- Hs-Mf 19 mer sense CCACCAUCCCCAUGACCGA 1360 1514 strand NR1H3-1449- Hs-Mf 19 mer sense CACCAUCCCCAUGACCGAC 1361 1515 strand NR1H3-1450- Hs-Mf 19 mer sense ACCAUCCCCAUGACCGACU 1362 1516 strand NR1H3-1451- Hs-Mf 19 mer sense CCAUCCCCAUGACCGACUG 1363 1517 strand NR1H3-1452- Hs-Mf- 19 mer sense CAUCCCCAUGACCGACUGA 1364 1518-1549 Mm strand NR1H3-1453- Hs-Mf- 19 mer sense AUCCCCAUGACCGACUGAU 1365 1519-1550 Mm strand NR1H3-1454- Hs-Mf- 19 mer sense UCCCCAUGACCGACUGAUG 1366 1520-1551 Mm strand NR1H3-1455- Hs-Mf- 19 mer sense CCCCAUGACCGACUGAUGU 1367 1521-1552 Mm strand NR1H3-1456- Hs-Mf- 19 mer sense CCCAUGACCGACUGAUGUU 1368 1522-1553 Mm strand NR1H3-1457- Hs-Mf- 19 mer sense CCAUGACCGACUGAUGUUC 1369 1523-1554 Mm strand NR1H3-1459- Hs-Mf- 19 mer sense AUGACCGACUGAUGUUCCC 1370 1525-1556 Mm strand NR1H3-1460- Hs-Mf- 19 mer sense UGACCGACUGAUGUUCCCA 1371 1526-1557 Mm strand NR1H3-1461- Hs-Mf- 19 mer sense GACCGACUGAUGUUCCCAC 1372 1527-1558 Mm strand NR1H3-1462- Hs-Mf- 19 mer sense ACCGACUGAUGUUCCCACG 1373 1528-1559 Mm strand NR1H3-1463- Hs-Mf- 19 mer sense CCGACUGAUGUUCCCACGG 1374 1529-1560 Mm strand NR1H3-1465- Hs-Mf- 19 mer sense GACUGAUGUUCCCACGGAU 1375 1531-1562 Mm strand NR1H3-1466- Hs-Mf- 19 mer sense ACUGAUGUUCCCACGGAUG 1376 1532-1563 Mm strand NR1H3-1468- Hs-Mf- 19 mer sense UGAUGUUCCCACGGAUGCU 1377 1534-1565 Mm strand NR1H3-1469- Hs-Mf- 19 mer sense GAUGUUCCCACGGAUGCUA 1378 1535-1566 Mm strand NR1H3-1471- Hs-Mf- 19 mer sense UGUUCCCACGGAUGCUAAU 1379 1537-1568 Mm strand NR1H3-1472- Hs-Mf- 19 mer sense GUUCCCACGGAUGCUAAUG 1380 1538-1569 Mm strand NR1H3-1473- Hs-Mf- 19 mer sense UUCCCACGGAUGCUAAUGA 1381 1539-1570 Mm strand NR1H3-1474- Hs-Mf- 19 mer sense UCCCACGGAUGCUAAUGAA 1382 1540-1571 Mm strand NR1H3-1475- Hs-Mf- 19 mer sense CCCACGGAUGCUAAUGAAA 1383 1541-1572 Mm strand NR1H3-1476- Hs-Mf- 19 mer sense CCACGGAUGCUAAUGAAAC 1384 1542-1573 Mm strand NR1H3-1477- Hs-Mf- 19 mer sense CACGGAUGCUAAUGAAACU 1385 1543-1574 Mm strand NR1H3-1478- Hs-Mf- 19 mer sense ACGGAUGCUAAUGAAACUG 1386 1544-1575 Mm strand NR1H3-1479- Hs-Mf- 19 mer sense CGGAUGCUAAUGAAACUGG 1387 1545-1576 Mm strand NR1H3-1480- Hs-Mf- 19 mer sense GGAUGCUAAUGAAACUGGU 1388 1546-1577 Mm strand NR1H3-1481- Hs-Mf- 19 mer sense GAUGCUAAUGAAACUGGUG 1389 1547-1578 Mm strand NR1H3-1483- Hs-Mf- 19 mer sense UGCUAAUGAAACUGGUGAG 1390 1549-1580 Mm strand NR1H3-1484- Hs-Mf- 19 mer sense GCUAAUGAAACUGGUGAGC 1391 1550-1581 Mm strand NR1H3-1485- Hs-Mf- 19 mer sense CUAAUGAAACUGGUGAGCC 1392 1551-1582 Mm strand NR1H3-1486- Hs-Mf- 19 mer sense UAAUGAAACUGGUGAGCCU 1393 1552-1583 Mm strand NR1H3-1487- Hs-Mf- 19 mer sense AAUGAAACUGGUGAGCCUC 1394 1553-1584 Mm strand NR1H3-1488- Hs-Mf- 19 mer sense AUGAAACUGGUGAGCCUCC 1395 1554-1585 Mm strand NR1H3-1489- Hs-Mf- 19 mer sense UGAAACUGGUGAGCCUCCG 1396 1555-1586 Mm strand NR1H3-1491- Hs-Mf- 19 mer sense AAACUGGUGAGCCUCCGGA 1397 1557-1588 Mm strand NR1H3-1492- Hs-Mf- 19 mer sense AACUGGUGAGCCUCCGGAC 1398 1558-1589 Mm strand NR1H3-1494- Hs-Mf 19 mer sense CUGGUGAGCCUCCGGACCC 1399 1560 strand NR1H3-1505- Hs-Mf- 19 mer sense CCGGACCCUGAGCAGCGUC 1400 1571-1602 Mm strand NR1H3-1507- Hs-Mf- 19 mer sense GGACCCUGAGCAGCGUCCA 1401 1573-1604 Mm strand NR1H3-1508- Hs-Mf 19 mer sense GACCCUGAGCAGCGUCCAC 1402 1574 strand NR1H3-1509- Hs-Mf 19 mer sense ACCCUGAGCAGCGUCCACU 1403 1575 strand NR1H3-1510- Hs-Mf 19 mer sense CCCUGAGCAGCGUCCACUC 1404 1576 strand NR1H3-1511- Hs-Mf- 19 mer sense CCUGAGCAGCGUCCACUCA 1405 1577-1608 Mm strand NR1H3-1512- Hs-Mf- 19 mer sense CUGAGCAGCGUCCACUCAG 1406 1578-1609 Mm strand NR1H3-1513- Hs-Mf- 19 mer sense UGAGCAGCGUCCACUCAGA 1407 1579-1610 Mm strand NR1H3-1514- Hs-Mf- 19 mer sense GAGCAGCGUCCACUCAGAG 1408 1580-1611 Mm strand NR1H3-1515- Hs-Mf- 19 mer sense AGCAGCGUCCACUCAGAGC 1409 1581-1612 Mm strand NR1H3-1516- Hs-Mf- 19 mer sense GCAGCGUCCACUCAGAGCA 1410 1582-1613 Mm strand NR1H3-1517- Hs-Mf- 19 mer sense CAGCGUCCACUCAGAGCAA 1411 1583-1614 Mm strand NR1H3-1518- Hs-Mf- 19 mer sense AGCGUCCACUCAGAGCAAG 1412 1584-1615 Mm strand NR1H3-1519- Hs-Mf- 19 mer sense GCGUCCACUCAGAGCAAGU 1413 1585-1616 Mm strand NR1H3-1520- Hs-Mf- 19 mer sense CGUCCACUCAGAGCAAGUG 1414 1586-1617 Mm strand NR1H3-1521- Hs-Mf- 19 mer sense GUCCACUCAGAGCAAGUGU 1415 1587-1618 Mm strand NR1H3-1522- Hs-Mf- 19 mer sense UCCACUCAGAGCAAGUGUU 1416 1588-1619 Mm strand NR1H3-1523- Hs-Mf- 19 mer sense CCACUCAGAGCAAGUGUUU 1417 1589-1620 Mm strand NR1H3-1525- Hs-Mf- 19 mer sense ACUCAGAGCAAGUGUUUGC 1418 1591-1622 Mm strand NR1H3-1526- Hs-Mf- 19 mer sense CUCAGAGCAAGUGUUUGCA 1419 1592-1623 Mm strand NR1H3-1527- Hs-Mf- 19 mer sense UCAGAGCAAGUGUUUGCAC 1420 1593-1624 Mm strand NR1H3-1528- Hs-Mf- 19 mer sense CAGAGCAAGUGUUUGCACU 1421 1594-1625 Mm strand NR1H3-1529- Hs-Mf- 19 mer sense AGAGCAAGUGUUUGCACUG 1422 1595-1626 Mm strand NR1H3-1530- Hs-Mf- 19 mer sense GAGCAAGUGUUUGCACUGC 1423 1596-1627 Mm strand NR1H3-1531- Hs-Mf- 19 mer sense AGCAAGUGUUUGCACUGCG 1424 1597-1628 Mm strand NR1H3-1532- Hs-Mf- 19 mer sense GCAAGUGUUUGCACUGCGU 1425 1598-1629 Mm strand NR1H3-1533- Hs-Mf- 19 mer sense CAAGUGUUUGCACUGCGUC 1426 1599-1630 Mm strand NR1H3-1534- Hs-Mf- 19 mer sense AAGUGUUUGCACUGCGUCU 1427 1600-1631 Mm strand NR1H3-1535- Hs-Mf- 19 mer sense AGUGUUUGCACUGCGUCUG 1428 1601-1632 Mm strand NR1H3-1536- Hs-Mf- 19 mer sense GUGUUUGCACUGCGUCUGC 1429 1602-1633 Mm strand NR1H3-1537- Hs-Mf- 19 mer sense UGUUUGCACUGCGUCUGCA 1430 1603-1634 Mm strand NR1H3-1538- Hs-Mf- 19 mer sense GUUUGCACUGCGUCUGCAG 1431 1604-1635 Mm strand NR1H3-1539- Hs-Mf- 19 mer sense UUUGCACUGCGUCUGCAGG 1432 1605-1636 Mm strand NR1H3-1540- Hs-Mf- 19 mer sense UUGCACUGCGUCUGCAGGA 1433 1606-1637 Mm strand NR1H3-1541- Hs-Mf- 19 mer sense UGCACUGCGUCUGCAGGAC 1434 1607-1638 Mm strand NR1H3-1542- Hs-Mf- 19 mer sense GCACUGCGUCUGCAGGACA 1435 1608-1639 Mm strand NR1H3-1543- Hs-Mf- 19 mer sense CACUGCGUCUGCAGGACAA 1436 1609-1640 Mm strand NR1H3-1544- Hs-Mf- 19 mer sense ACUGCGUCUGCAGGACAAA 1437 1610-1641 Mm strand NR1H3-1545- Hs-Mf- 19 mer sense CUGCGUCUGCAGGACAAAA 1438 1611-1642 Mm strand NR1H3-1546- Hs-Mf- 19 mer sense UGCGUCUGCAGGACAAAAA 1439 1612-1643 Mm strand NR1H3-1547- Hs-Mf- 19 mer sense GCGUCUGCAGGACAAAAAG 1440 1613-1644 Mm strand NR1H3-1548- Hs-Mf- 19 mer sense CGUCUGCAGGACAAAAAGC 1441 1614-1645 Mm strand NR1H3-1549- Hs-Mf- 19 mer sense GUCUGCAGGACAAAAAGCU 1442 1615-1646 Mm strand NR1H3-1550- Hs-Mf- 19 mer sense UCUGCAGGACAAAAAGCUC 1443 1616-1647 Mm strand NR1H3-1551- Hs-Mf- 19 mer sense CUGCAGGACAAAAAGCUCC 1444 1617-1648 Mm strand NR1H3-1553- Hs-Mf- 19 mer sense GCAGGACAAAAAGCUCCCA 1445 1619-1650 Mm strand NR1H3-1554- Hs-Mf- 19 mer sense CAGGACAAAAAGCUCCCAC 1446 1620-1651 Mm strand NR1H3-1555- Hs-Mf- 19 mer sense AGGACAAAAAGCUCCCACC 1447 1621-1652 Mm strand NR1H3-1556- Hs-Mf- 19 mer sense GGACAAAAAGCUCCCACCG 1448 1622-1653 Mm strand NR1H3-1558- Hs-Mf- 19 mer sense ACAAAAAGCUCCCACCGCU 1449 1624-1655 Mm strand NR1H3-1559- Hs-Mf- 19 mer sense CAAAAAGCUCCCACCGCUG 1450 1625-1656 Mm strand NR1H3-1560- Hs-Mf- 19 mer sense AAAAAGCUCCCACCGCUGC 1451 1626-1657 Mm strand NR1H3-1561- Hs-Mf- 19 mer sense AAAAGCUCCCACCGCUGCU 1452 1627-1658 Mm strand NR1H3-1562- Hs-Mf 19 mer sense AAAGCUCCCACCGCUGCUC 1453 1628 strand NR1H3-1563- Hs-Mf 19 mer sense AAGCUCCCACCGCUGCUCU 1454 1629 strand NR1H3-1564- Hs-Mf 19 mer sense AGCUCCCACCGCUGCUCUC 1455 1630 strand NR1H3-1565- Hs-Mf 19 mer sense GCUCCCACCGCUGCUCUCU 1456 1631 strand NR1H3-1567- Hs-Mf 19 mer sense UCCCACCGCUGCUCUCUGA 1457 1633 strand NR1H3-1569- Hs-Mf 19 mer sense CCACCGCUGCUCUCUGAGA 1458 1635 strand NR1H3-1570- Hs-Mf 19 mer sense CACCGCUGCUCUCUGAGAU 1459 1636 strand NR1H3-1572- Hs-Mf- 19 mer sense CCGCUGCUCUCUGAGAUCU 1460 1638-1669 Mm strand NR1H3-1573- Hs-Mf- 19 mer sense CGCUGCUCUCUGAGAUCUG 1461 1639-1670 Mm strand NR1H3-1574- Hs-Mf- 19 mer sense GCUGCUCUCUGAGAUCUGG 1462 1640-1671 Mm strand NR1H3-1577- Hs-Mf- 19 mer sense GCUCUCUGAGAUCUGGGAU 1463 1643-1674 Mm strand NR1H3-1579- Hs-Mf- 19 mer sense UCUCUGAGAUCUGGGAUGU 1464 1645-1676 Mm strand NR1H3-1580- Hs-Mf- 19 mer sense CUCUGAGAUCUGGGAUGUG 1465 1646-1677 Mm strand NR1H3-1581- Hs-Mf- 19 mer sense UCUGAGAUCUGGGAUGUGC 1466 1647-1678 Mm strand NR1H3-1582- Hs-Mf- 19 mer sense CUGAGAUCUGGGAUGUGCA 1467 1648-1679 Mm strand NR1H3-1583- Hs-Mf- 19 mer sense UGAGAUCUGGGAUGUGCAC 1468 1649-1680 Mm strand NR1H3-1584- Hs-Mf- 19 mer sense GAGAUCUGGGAUGUGCACG 1469 1650-1681 Mm strand NR1H3-1585- Hs-Mf- 19 mer sense AGAUCUGGGAUGUGCACGA 1470 1651-1682 Mm strand NR1H3-1586- Hs-Mf- 19 mer sense GAUCUGGGAUGUGCACGAA 1471 1652-1683 Mm strand NR1H3-1587- Hs-Mf- 19 mer sense AUCUGGGAUGUGCACGAAU 1472 1653-1684 Mm strand NR1H3-1588- Hs-Mf- 19 mer sense UCUGGGAUGUGCACGAAUG 1473 1654-1685 Mm strand NR1H3-1589- Hs-Mf- 19 mer sense CUGGGAUGUGCACGAAUGA 1474 1655-1686 Mm strand NR1H3-1590- Hs-Mf- 19 mer sense UGGGAUGUGCACGAAUGAC 1475 1656-1687 Mm strand NR1H3-1591- Hs-Mf- 19 mer sense GGGAUGUGCACGAAUGACU 1476 1657-1688 Mm strand NR1H3-1592- Hs-Mf- 19 mer sense GGAUGUGCACGAAUGACUG 1477 1658-1689 Mm strand NR1H3-1593- Hs-Mf- 19 mer sense GAUGUGCACGAAUGACUGU 1478 1659-1690 Mm strand NR1H3-1656- Hs-Mf 19 mer sense UGGUGGCUGCCUCCUAGAA 1479 1720 strand NR1H3-1657- Hs-Mf 19 mer sense GGUGGCUGCCUCCUAGAAG 1480 1721 strand NR1H3-1658- Hs-Mf 19 mer sense GUGGCUGCCUCCUAGAAGU 1481 1722 strand NR1H3-1659- Hs-Mf 19 mer sense UGGCUGCCUCCUAGAAGUG 1482 1723 strand NR1H3-1660- Hs-Mf 19 mer sense GGCUGCCUCCUAGAAGUGG 1483 1724 strand NR1H3-1661- Hs-Mf 19 mer sense GCUGCCUCCUAGAAGUGGA 1484 1725 strand NR1H3-1662- Hs-Mf 19 mer sense CUGCCUCCUAGAAGUGGAA 1485 1726 strand NR1H3-1663- Hs-Mf 19 mer sense UGCCUCCUAGAAGUGGAAC 1486 1727 strand NR1H3-1664- Hs-Mf 19 mer sense GCCUCCUAGAAGUGGAACA 1487 1728 strand NR1H3-1665- Hs-Mf 19 mer sense CCUCCUAGAAGUGGAACAG 1488 1729 strand NR1H3-1666- Hs-Mf 19 mer sense CUCCUAGAAGUGGAACAGA 1489 1730 strand NR1H3-1667- Hs-Mf 19 mer sense UCCUAGAAGUGGAACAGAC 1490 1731 strand NR1H3-1668- Hs-Mf 19 mer sense CCUAGAAGUGGAACAGACU 1491 1732 strand NR1H3-1669- Hs-Mf 19 mer sense CUAGAAGUGGAACAGACUG 1492 1733 strand NR1H3-1671- Hs-Mf 19 mer sense AGAAGUGGAACAGACUGAG 1493 1735 strand NR1H3-1677- Hs-Mf- 19 mer sense GGAACAGACUGAGAAGGGC 1494 1741-1768 Mm strand NR1H3-1679- Hs-Mf- 19 mer sense AACAGACUGAGAAGGGCAA 1495 1743-1770 Mm strand NR1H3-1680- Hs-Mf- 19 mer sense ACAGACUGAGAAGGGCAAA 1496 1744-1771 Mm strand NR1H3-1681- Hs-Mf- 19 mer sense CAGACUGAGAAGGGCAAAC 1497 1745-1772 Mm strand NR1H3-1682- Hs-Mf- 19 mer sense AGACUGAGAAGGGCAAACA 1498 1746-1773 Mm strand NR1H3-1683- Hs-Mf- 19 mer sense GACUGAGAAGGGCAAACAU 1499 1747-1774 Mm strand NR1H3-1684- Hs-Mf- 19 mer sense ACUGAGAAGGGCAAACAUU 1500 1748-1775 Mm strand NR1H3-1685- Hs-Mf- 19 mer sense CUGAGAAGGGCAAACAUUC 1501 1749-1776 Mm strand NR1H3-1686- Hs-Mf- 19 mer sense UGAGAAGGGCAAACAUUCC 1502 1750-1777 Mm strand NR1H3-1687- Hs-Mf- 19 mer sense GAGAAGGGCAAACAUUCCU 1503 1751-1778 Mm strand NR1H3-1728- Hs-Mf 19 mer sense CCCGUGGCAUUAAAAGAGA 1504 1792 strand NR1H3-1729- Hs-Mf 19 mer sense CCGUGGCAUUAAAAGAGAG 1505 1793 strand NR1H3-1730- Hs-Mf 19 mer sense CGUGGCAUUAAAAGAGAGU 1506 1794 strand NR1H3-1731- Hs-Mf 19 mer sense GUGGCAUUAAAAGAGAGUC 1507 1795 strand NR1H3-1732- Hs-Mf- 19 mer sense UGGCAUUAAAAGAGAGUCA 1508 1796-1826 Mm strand NR1H3-1209- Hs-Mf- 19 mer sense CUCAAGGAUUUCAGUUAUA 1509 1229-1306 Mm strand NR1H3-1210- Hs-Mf- 19 mer sense UCAAGGAUUUCAGUUAUAA 1510 1230-1307 Mm strand NR1H3-1594- Hs-Mf- 19 mer sense AUGUGCACGAAUGACUGUU 1511 1660-1691 Mm strand NR1H3-1209- Hs-Mf- 19 mer UAUAACUGAAAUCCUUGAG 1512 1229-1306 Mm antisense strand NR1H3-1210- Hs-Mf- 19 mer UUAUAACUGAAAUCCUUGA 1513 1230-1307 Mm antisense strand NR1H3-1515- Hs-Mf- 19 mer GCUCUGAGUGGACGCUGCU 1514 1581-1612 Mm antisense strand NR1H3-1594- Hs-Mf- 19 mer AACAGUCAUUCGUGCACAU 1515 1660-1691 Mm antisense strand DNA Homo ATGGAATTCC CCATTGGATC 1516 sapiens CCTCGAAACT AACAACTTCC GTCGCTTTAC TCCGGAGTCA CTGGTGGAGA TAGAGAAGCA AATTGCTGCC AAGCAGGGAA CAAAGAAAGC CAGAGAGAAG CATAGGGAGC AGAAGGACCA AGAAGAGAAG CCTCGGCCCC AGCTGGACTT GAAAGCCTGC AACCAGCTGC CCAAGTTCTA TGGTGAGCTC CCAGCAGAAC TGATCGGGGA GCCCCTGGAG GATCTAGATC CGTTCTACAG CACACACCGG ACATTTATGG TGCTGAACAA AGGGAGGACC ATTTCCCGGT TTAGTGCCAC TCGGGCCCTG TGGCTATTCA GTCCTTTCAA CCTGATCAGA AGAACGGCCA TCAAAGTGTC TGTCCACTCG TGGTTCAGTT TATTTATTAC GGTCACTATT TTGGTTAATT GTGTGTGCAT GACCCGAACT GACCTTCCAG AGAAAATTGA ATATGTCTTC ACTGTCATTT ACACCTTTGA AGCCTTGATA AAGATACTGG CAAGAGGATT TTGTCTAAAT GAGTTCACGT ACCTGAGAGA TCCTTGGAAC TGGCTGGATT TTAGCGTCAT TACCCTGGCA TATGTTGGCA CAGCAATAGA TCTCCGTGGG ATCTCAGGCC TGCGGACATT CAGAGTTCTT AGAGCATTAA AAACAGTTTC TGTGATCCCA GGCCTGAAGG TCATTGTGGG GGCCCTGATT CACTCAGTGA AGAAACTGGC TGATGTGACC ATCCTCACCA TCTTCTGCCT AAGTGTTTTT GCCTTGGTGG GGCTGCAACT CTTCAAGGGC AACCTCAAAA ATAAATGTGT CAAGAATGAC ATGGCTGTCA ATGAGACAAC CAACTACTCA TCTCACAGAA AACCAGATAT CTACATAAAT AAGCGAGGCA CTTCTGACCC CTTACTGTGT GGCAATGGAT CTGACTCAGG CCACTGCCCT GATGGTTATA TCTGCCTTAA AACTTCTGAC AACCCGGATT TTAACTACAC CAGCTTTGAT TCCTTTGCTT GGGCTTTCCT CTCACTGTTC CGCCTCATGA CACAGGATTC CTGGGAACGCCTCTACCAGC AGACCCTGAG GACTTCTGGG AAAATCTATA TGATCTTTTT TGTGCTCGTA ATCTTCCTGG GATCTTTCTA CCTGGTCAAC TTGATCTTGG CTGTAGTCAC CATGGCGTAT GAGGAGCAGA ACCAGGCAAC CACTGATGAA ATTGAAGCAA AGGAGAAGAA GTTCCAGGAG GCCCTCGAGA TGCTCCGGAA GGAGCAGGAG GTGCTAGCAG CACTAGGGAT TGACACAACC TCTCTCCACT CCCACAATGG ATCACCTTTA ACCTCCAAAA ATGCCAGTGA GAGAAGGCAT AGAATAAAGC CAAGAGTGTC AGAGGGCTCC ACAGAAGACA ACAAATCACC CCGCTCTGAT CCTTACAACC AGCGCAGGAT GTCTTTTCTA GGCCTCGCCT CTGGAAAACG CCGGGCTAGT CATGGCAGTG TGTTCCATTT CCGGTCCCCT GGCCGAGATA TCTCACTCCC TGAGGGAGTC ACAGATGATG GAGTCTTTCC TGGAGACCAC GAAAGCCATC GGGGCTCTCT GCTGCTGGGT GGGGGTGCTG GCCAGCAAGG CCCCCTCCCT AGAAGCCCTC TTCCTCAACC CAGCAACCCT GACTCCAGGC ATGGAGAAGA TGAACACCAA CCGCCGCCCA CTAGTGAGCT TGCCCCTGGA GCTGTCGATG TCTCGGCATT CGATGCAGGA CAAAAGAAGA CTTTCTTGTC AGCAGAATAC TTAGATGAAC CTTTCCGGGC CCAAAGGGCA ATGAGTGTTG TCAGTATCAT AACCTCCGTC CTTGAGGAAC TCGAGGAGTC TGAACAGAAG TGCCCACCCT GCTTGACCAG CTTGTCTCAG AAGTATCTGA TCTGGGATTG CTGCCCCATG TGGGTGAAGC TCAAGACAAT TCTCTTTGGG CTTGTGACGG ATCCCTTTGC AGAGCTCACC ATCACCTTGT GCATCGTGGT GAACACCATC TTCATGGCCA TGGAGCACCA TGGCATGAGC CCTACCTTCG AAGCCATGCT CCAGATAGGC AACATCGTCT TTACCATATT TTTTACTGCT GAAATGGTCT TCAAAATCAT TGCCTTCGAC CCATACTATT ATTTCCAGAA GAAGTGGAAT ATCTTTGACT GCATCATCGT CACTGTGAGT CTGCTAGAGC TGGGCGTGGC CAAGAAGGGA AGCCTGTCTG TGCTGCGGAG CTTCCGCTTG CTGCGCGTAT TCAAGCTGGC CAAATCCTGG CCCACCTTAA ACACACTCAT CAAGATCATC GGAAACTCAG TGGGGGCACT GGGGAACCTC ACCATCATCC TGGCCATCAT TGTCTTTGTC TTTGCTCTGG TTGGCAAGCA GCTCCTAGGG GAAAACTACC GTAACAACCG AAAAAATATC TCCGCGCCCC ATGAAGACTG GCCCCGCTGG CACATGCACG ACTTCTTCCA CTCTTTCCTC ATTGTCTTCC GTATCCTCTG TGGAGAGTGG ATTGAGAACA TGTGGGCCTG CATGGAAGTT GGCCAAAAAT CCATATGCCT CATCCTTTTC TTGACGGTGA TGGTGCTAGG GAACCTGGTG GTGCTTAACC TGTTCATCGC CCTGCTATTG AACTCTTTCA GTGCTGACAA CCTCACAGCC CCGGAGGACG ATGGGGAGGT GAACAACCTG CAGGTGGCCC TGGCACGGAT CCAGGTCTTT GGCCATCGTA CCAAACAGGC TCTTTGCAGC TTCTTCAGCA GGTCCTGCCC ATTCCCCCAG CCCAAGGCAG AGCCTGAGCT GGTGGTGAAA CTCCCACTCT CCAGCTCCAA GGCTGAGAAC CACATTGCTG CCAACACTGC CAGGGGGAGC TCTGGAGGGC TCCAAGCTCC CAGAGGCCCC AGGGATGAGC ACAGTGACTT CATCGCTAAT CCGACTGTGT GGGTCTCTGT GCCCATTGCT GAGGGTGAAT CTGATCTTGA TGACTTGGAG GATGATGGTG GGGAAGATGC TCAGAGCTTC CAGCAGGAAG TGATCCCCAA AGGACAGCAG GAGCAGCTGC AGCAAGTCGA GAGGTGTGGG GACCACCTGA CACCCAGGAG CCCAGGCACT GGAACATCTT CTGAGGACCT GGCTCCATCC CTGGGTGAGA CGTGGAAAGA TGAGTCTGTT CCTCAGGTCC CTGCTGAGGG AGTGGACGAC ACAAGCTCCT CTGAGGGCAG CACGGTGGAC TGCCTAGATC CTGAGGAAAT CCTGAGGAAG ATCCCTGAGC TGGCAGATGA CCTGGAAGAA CCAGATGACT GCTTCACAGA AGGATGCATT CGCCACTGTC CCTGCTGCAA ACTGGATACC ACCAAGAGTC CATGGGATGT GGGCTGGCAG GTGCGCAAGA CTTGCTACCG TATCGTGGAG CACAGCTGGT TTGAGAGCTT CATCATCTTC ATGATCCTGC TCAGCAGTGG ATCTCTGGCC TTTGAAGACT ATTACCTGGA CCAGAAGCCC ACGGTGAAAG CTTTGCTGGA GTACACTGAC AGGGTCTTCA CCTTTATCTT TGTGTTCGAG ATGCTGCTTA AGTGGGTGGC CTATGGCTTC AAAAAGTACT TCACCAATGC CTGGTGCTGG CTGGACTTCC TCATTGTGAA TATCTCACTG ATAAGTCTCA CAGCGAAGAT TCTGGAATAT TCTGAAGTGG CTCCCATCAA AGCCCTTCGA ACCCTTCGCG CTCTGCGGCC ACTGCGGGCT CTTTCTCGAT TTGAAGGCAT GCGGGTGGTG GTGGATGCCC TGGTGGGCGC CATCCCATCC ATCATGAATG TCCTCCTCGT CTGCCTCATC TTCTGGCTCA TCTTCAGCAT CATGGGTGTG AACCTCTTCG CAGGGAAGTT TTGGAGGTGC ATCAACTATA CCGATGGAGA GTTTTCCCTT GTACCTTTGT CGATTGTGAA TAACAAGTCT GACTGCAAGA TTCAAAACTC CACTGGCAGC TTCTTCTGGG TCAATGTGAA AGTCAACTTT GATAATGTTG CAATGGGTTA CCTTGCACTT CTGCAGGTGG CAACCTTTAA AGGCTGGATG GACATTATGT ATGCAGCTGT TGATTCCCGG GAGGTCAACA TGCAACCCAA GTGGGAGGAC AACGTGTACA TGTATTTGTA CTTTGTCATC TTCATCATTT TTGGAGGCTT CTTCACACTG AATCTCTTTG TTGGGGTCAT AATTGACAAC TTCAATCAAC AGAAAAAAAA GTTAGGGGGC CAGGACATCT TCATGACAGA GGAGCAGAAG AAATACTACA ATGCCATGAA GAAGTTGGGC TCCAAGAAGC CCCAGAAGCC CATCCCACGG CCCCTGAACA AGTTCCAGGG TTTTGTCTTT GACATCGTGA CCAGACAAGC TTTTGACATC ACCATCATGG TCCTCATCTG CCTCAACATG ATCACCATGA TGGTGGAGAC TGATGACCAA AGTGAAGAAA AGACGAAAAT TCTGGGCAAA ATCAACCAGT TCTTTGTGGC CGTCTTCACA GGCGAATGTG TCATGAAGAT GTTCGCTTTG AGGCAGTACT ACTTCACAAA TGGCTGGAAT GTGTTTGACT TCATTGTGGT GGTTCTCTCC ATTGCGAGCC TGATTTTTTC TGCAATTCTT AAGTCACTTC AAAGTTACTT CTCCCCAACG CTCTTCAGAG TCATCCGCCT GGCCCGAATT GGCCGCATCC TCAGACTGAT CCGAGCGGCC AAGGGGATCC GCACACTGCT CTTTGCCCTC ATGATGTCCC TGCCTGCCCT CTTCAACATC GGGCTGTTGC TATTCCTTGT CATGTTCATC TACTCTATCT TCGGTATGTC CAGCTTTCCC CATGTGAGGT GGGAGGCTGG CATCGACGAC ATGTTCAACT TCCAGACCTT CGCCAACAGC ATGCTGTGCC TCTTCCAGAT TACCACGTCG GCCGGCTGGG ATGGCCTCCT CAGCCCCATC CTCAACACAG GGCCCCCCTA CTGTGACCCC AATCTGCCCA ACAGCAATGG CACCAGAGGG GACTGTGGGA GCCCAGCCGT AGGCATCATC TTCTTCACCA CCTACATCAT CATCTCCTTC CTCATCGTGG TCAACATGTA CATTGCAGTG ATTCTGGAGA ACTTCAATGT GGCCACGGAG GAGAGCACTG AGCCCCTGAG TGAGGACGAC TTTGACATGT TCTATGAGAC CTGGGAGAAG TTTGACCCAG AGGCCACTCA GTTTATTACC TTTTCTGCTC TCTCGGACTT TGCAGACACT CTCTCTGGTC CCCTGAGAAT CCCAAAACCC AATCGAAATA TACTGATCCA GATGGACCTG CCTTTGGTCC CTGGAGATAA GATCCACTGC TTGGACATCC TTTTTGCTTT CACCAAGAAT GTCCTAGGAG AATCCGGGGA GTTGGATTCT CTGAAGGCAA ATATGGAGGA GAAGTTTATG GCAACTAATC TTTCAAAATC ATCCTATGAA CCAATAGCAA CCACTCTCCG ATGGAAGCAA GAAGACATTT CAGCCACTGT CATTCAAAAG GCCTATCGGA GCTATGTGCT GCACCGCTCC ATGGCACTCT CTAACACCCC ATGTGTGCCC AGAGCTGAGG AGGAGGCTGC ATCACTCCCA GATGAAGGTT TTGTTGCATT CACAGCAAAT GAAAATTGTG TACTCCCAGA CAAATCTGAA ACTGCTTCTG CCACATCATT CCCACCGTCC TATGAGAGTG TCACTAGAGG CCTTAGTGAT AGAGTCAACA TGAGGACATC TAGCTCAATA CAAAATGAAG ATGAAGCCAC CAGTATGGAG CTGATTGCCC CTGGGCCCTA GTGA Forward-942 Artificial GTCTCTGTGCAGGAGATAGTTG 1517 Sequence Reverse-1399 Artificial GGAGGCTCACCAGTTTCATTA 1518 Sequence NR1H3-1207- Hs-Mf- 36 mer sense UCCUCAAGGAUUUCAGUUAAGCA 1519 1227-1304 Mm strand GCCGAAAGGCUGC NR1H3-1220- Hs-Mf- 36 mer sense CAGUUAUAACCGGGAAGACAGCA 1520 1240-1317 Mm strand GCCGAAAGGCUGC NR1H3-1224- Hs-Mf- 36 mer sense UAUAACCGGGAAGACUUUGAGC 1521 1244-1321 Mm strand AGCCGAAAGGCUGC NR1H3-1244- Hs-Mf- 36 mer sense CAAAGCAGGGCUGCAAGUGAGCA 1522 1264-1341 Mm strand GCCGAAAGGCUGC NR1H3-1252- Hs-Mf- 36 mer sense GGCUGCAAGUGGAAUUCAUAGC 1523 1272-1349 Mm strand AGCCGAAAGGCUGC NR1H3-1259- Hs-Mf- 36 mer sense AGUGGAAUUCAUCAACCCCAGCA 1524 1279-1356 Mm strand GCCGAAAGGCUGC NR1H3-1265- Hs-Mf- 36 mer sense AUUCAUCAACCCCAUCUUCAGCA 1525 1285-1362 Mm strand GCCGAAAGGCUGC NR1H3-1266- Hs-Mf- 36 mer sense UUCAUCAACCCCAUCUUCGAGCA 1526 1286-1363 Mm strand GCCGAAAGGCUGC NR1H3-1429- Hs-Mf- 36 mer sense UGCAUGCCUACGUCUCCAUAGCA 1527 1495-1526 Mm strand GCCGAAAGGCUGC NR1H3-1433- Hs-Mf- 36 mer sense UGCCUACGUCUCCAUCCACAGCA 1528 1499-1530 Mm strand GCCGAAAGGCUGC NR1H3-1437- Hs-Mf- 36 mer sense UACGUCUCCAUCCACCAUCAGCA 1529 1503-1534 Mm strand GCCGAAAGGCUGC NR1H3-1439- Hs-Mf- 36 mer sense CGUCUCCAUCCACCAUCCCAGCA 1530 1505-1536 Mm strand GCCGAAAGGCUGC NR1H3-1446- Hs-Mf- 36 mer sense AUCCACCAUCCCCAUGACCAGCA 1531 1512-1543 Mm strand GCCGAAAGGCUGC NR1H3-1463- Hs-Mf- 36 mer sense CCGACUGAUGUUCCCACGGAGCA 1532 1529-1560 Mm strand GCCGAAAGGCUGC NR1H3-1475- Hs-Mf- 36 mer sense CCCACGGAUGCUAAUGAAAAGCA 1533 1541-1572 Mm strand GCCGAAAGGCUGC NR1H3-1479- Hs-Mf- 36 mer sense CGGAUGCUAAUGAAACUGGAGC 1534 1545-1576 Mm strand AGCCGAAAGGCUGC NR1H3-1481- Hs-Mf- 36 mer sense GAUGCUAAUGAAACUGGUGAGC 1535 1547-1578 Mm strand AGCCGAAAGGCUGC NR1H3-1485- Hs-Mf- 36 mer sense CUAAUGAAACUGGUGAGCCAGCA 1536 1551-1582 Mm strand GCCGAAAGGCUGC NR1H3-1515- Hs-Mf- 36 mer sense AGCAGCGUCCACUCAGAGCAGCA 1537 1581-1612 Mm strand GCCGAAAGGCUGC NR1H3-1517- Hs-Mf- 36 mer sense CAGCGUCCACUCAGAGCAAAGCA 1538 1583-1614 Mm strand GCCGAAAGGCUGC NR1H3-1518- Hs-Mf- 36 mer sense AGCGUCCACUCAGAGCAAGAGCA 1539 1584-1615 Mm strand GCCGAAAGGCUGC NR1H3-1533- Hs-Mf- 36 mer sense CAAGUGUUUGCACUGCGUCAGCA 1540 1599-1630 Mm strand GCCGAAAGGCUGC NR1H3-1535- Hs-Mf- 36 mer sense AGUGUUUGCACUGCGUCUGAGCA 1541 1601-1632 Mm strand GCCGAAAGGCUGC NR1H3-1545- Hs-Mf- 36 mer sense CUGCGUCUGCAGGACAAAAAGCA 1542 1611-1642 Mm strand GCCGAAAGGCUGC NR1H3-1554- Hs-Mf- 36 mer sense CAGGACAAAAAGCUCCCACAGCA 1543 1620-1651 Mm strand GCCGAAAGGCUGC NR1H3-1581- Hs-Mf- 36 mer sense UCUGAGAUCUGGGAUGUGCAGC 1544 1647-1678 Mm strand AGCCGAAAGGCUGC NR1H3-1586- Hs-Mf- 36 mer sense GAUCUGGGAUGUGCACGAAAGC 1545 1652-1683 Mm strand AGCCGAAAGGCUGC NR1H3-1587- Hs-Mf- 36 mer sense AUCUGGGAUGUGCACGAAUAGC 1546 1653-1684 Mm strand AGCCGAAAGGCUGC NR1H3-1588- Hs-Mf- 36 mer sense UCUGGGAUGUGCACGAAUGAGC 1547 1654-1685 Mm strand AGCCGAAAGGCUGC NR1H3-1663- Hs-Mf 36 mer sense UGCCUCCUAGAAGUGGAACAGCA 1548 1727 strand GCCGAAAGGCUGC NR1H3-1671- Hs-Mf 36 mer sense AGAAGUGGAACAGACUGAGAGC 1549 1735 strand AGCCGAAAGGCUGC NR1H3-1684- Hs-Mf- 36 mer sense ACUGAGAAGGGCAAACAUUAGC 1550 1748-1775 Mm strand AGCCGAAAGGCUGC NR1H3-1731- Hs-Mf 36 mer sense GUGGCAUUAAAAGAGAGUCAGC 1551 1795 strand AGCCGAAAGGCUGC NR1H3-1732- Hs-Mf- 36 mer sense UGGCAUUAAAAGAGAGUCAAGC 1552 1796-1826 Mm strand AGCCGAAAGGCUGC 

1. A double stranded RNAi oligonucleotide (dsRNAi) for reducing NR1H3 expression, comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, and wherein (i) the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 786 and 874, respectively; (ii) the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 787 and 875, respectively; (iii) the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1537 and 929, respectively; or (iv) the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 813 and 901, respectively.
 2. The double stranded RNAi oligonucleotide (dsRNAi) of claim 1, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 786 and 874, respectively.
 3. The double stranded RNAi oligonucleotide (dsRNAi) of claim 1, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 787 and 875, respectively.
 4. The double stranded RNAi oligonucleotide (dsRNAi) of claim 1, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 1537 and 929, respectively.
 5. The double stranded RNAi oligonucleotide (dsRNAi) of claim 1, wherein the sense and antisense strands comprise the nucleotide sequences set forth in SEQ ID NOs: 813 and 901, respectively.
 6. The double stranded RNAi oligonucleotide (dsRNAi) of claim 1, wherein the 3′ end of the sense strand comprises a stem-loop set forth as S1-L-S2, and wherein (i) S1 is complementary to S2, and S1 and S2 have the same length and are each 1-10 nucleotides in length; and (ii) L forms a loop between S1 and S2 of 3-5 nucleotides in length.
 7. The double stranded RNAi oligonucleotide (dsRNAi) of claim 6, wherein (i) S1 and S2 are 6 nucleotides in length; and (ii) L is a triloop or a tetraloop.
 8. The double stranded RNAi oligonucleotide (dsRNAi) of claim 7, wherein L is a tetraloop comprising the sequence 5′-GAAA-3′.
 9. The double stranded RNAi oligonucleotide (dsRNAi) of claim 6, wherein the stem-loop comprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 1121).
 10. The double stranded RNAi oligonucleotide (dsRNAi) of claim 6, wherein at least one nucleotide of the oligonucleotide is conjugated to one or more targeting ligands.
 11. The double stranded RNAi oligonucleotide (dsRNAi) of claim 10, wherein each targeting ligand comprises a carbohydrate, amino sugar, cholesterol, polypeptide or lipid.
 12. The double stranded RNAi oligonucleotide (dsRNAi) of claim 10, wherein the targeting ligand is a hepatocyte targeting ligand and each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety.
 13. The double stranded RNAi oligonucleotide (dsRNAi) of claim 12, wherein the N-acetylgalactosamine (GalNAc) moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety.
 14. The double stranded RNAi oligonucleotide (dsRNAi) of claim 10, wherein the stem loop comprises one or more targeting ligands conjugated to one or more nucleotides of the stem loop or the loop comprises one or more targeting ligands conjugated to one or more nucleotides of the loop.
 15. The double stranded RNAi oligonucleotide (dsRNAi) of claim 14, wherein the one or more targeting ligands is conjugated to one or more nucleotides of the loop, wherein the loop comprises 4 nucleotides numbered 1-4 from 5′ to 3′, wherein nucleotides at positions 2, 3, and 4 each comprise one or more targeting ligands, and wherein the targeting ligands are the same or different.
 16. The double stranded RNAi oligonucleotide (dsRNAi) of claim 14, wherein the targeting ligand is a hepatocyte targeting ligand and each targeting ligand comprises a N-acetylgalactosamine (GalNAc) moiety.
 17. The double stranded RNAi oligonucleotide (dsRNAi) of claim 16, wherein the N-acetylgalactosamine (GalNAc) moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety or a tetravalent GalNAc moiety.
 18. The double stranded RNAi oligonucleotide (dsRNAi) of claim 14, wherein the targeting ligand is a hepatocyte targeting ligand and up to 4 nucleotides of L of the stem-loop are each conjugated to a monovalent GalNAc moiety.
 19. The double stranded RNAi oligonucleotide (dsRNAi) of claim 6, comprising at least one modified nucleotide and said modified nucleotide comprises a 2′-modification selected from the group consisting of 2′-aminoethyl, 2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and 2′-deoxy-2′-fluoro-β-d-arabinonucleic acid.
 20. The double stranded RNAi oligonucleotide (dsRNAi) of claim 19, wherein all nucleotides of the oligonucleotide are modified, and the modification is 2′-fluoro and 2′-O-methyl.
 21. The double stranded RNAi oligonucleotide (dsRNAi) of claim 19, wherein the sense strand comprises 36 nucleotides with positions 1-36 from 5′ to 3′, wherein positions 8-11 comprise a 2′-fluoro modification; the antisense strand comprises 22 nucleotides with positions 1-22 from 5′ to 3′, and wherein positions 2, 3, 4, 5, 7, 10, and 14 comprise a 2′-fluoro modification; and the remaining nucleotides comprise a 2′-O-methyl modification.
 22. The double stranded RNAi oligonucleotide (dsRNAi) of claim 21, wherein (i) the oligonucleotide comprises at least one phosphorothioate linkage, wherein (a) the antisense strand comprises a phosphorothioate linkage (i) between positions 1 and 2, and between positions 2 and 3; or (ii) between positions 1 and 2, between positions 2 and 3, and between positions 3 and 4, wherein positions are numbered 1-4 from 5′ to 3′; or (b) the antisense strand is 22 nucleotides in length, and wherein the antisense strand comprises a phosphorothioate linkage between positions 20 and 21 and between positions 21 and 22, wherein positions are numbered 1-22 from 5′ to 3′, or (ii) the antisense strand comprises a phosphorylated nucleotide at the 5′ terminus, selected from uridine and adenosine, or (iii) the 4′-carbon of the sugar of the 5′-nucleotide of the antisense strand comprises a phosphate analog, wherein the phosphate analog is a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy, or (iv) the antisense strand comprises an overhang sequence at the 3′ terminus, and wherein the overhang sequence is 2 nucleotides in length selected from the group consisting of AA, GG, AG, and GA.
 23. A double stranded RNAi oligonucleotide (dsRNAi) for reducing NR1H3 expression, comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, wherein (i) the sense strand comprises the sequence and all of the modifications of 5′-mCs-mU-mC-mA-mA-mG-mG-fA-fU-fU-fU-mC-mA-mG-mU-mU-mA-mU-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 963), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fAs-fU-fA-mA-fC-mU-mG-fA-mA-mA-mU-fC-mC-mU-mU-mG-mA-mGs-mGs-mG-3′ (SEQ ID NO: 1051), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

(ii) the sense strand comprises the sequence and all of the modifications of 5′-mUs-mC-mA-mA-mG-mG-mA-fU-fU-fU-fC-mA-mG-mU-mU-mA-mU-mA-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 964), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fUs-fA-fU-mA-fA-mC-mU-fG-mA-mA-mA-fU-mC-mC-mU-mU-mG-mAs-mGs-mG-3′ (SEQ ID NO: 1052), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

(iii) the sense strand comprises the sequence and all of the modifications of 5′-mAs-mG-mC-mA-mG-mC-mG-fU-fC-fC-fA-mC-mU-mC-mA-mG-mA-mG-mC-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1006), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fGs-fCs-fU-fC-mU-fG-mA-mG-fU-mG-mG-mA-fC-mG-mC-mU-mG-mC-mUs-mGs-mG-3′ (SEQ ID NO: 1094), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

or (iv) the sense strand comprises the sequence and all of the modifications of 5′-mAs-mU-mG-mU-mG-mC-mA-fC-fG-fA-fA-mU-mG-mA-mC-mU-mG-mU-mU-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1018), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fAs-fAs-fC-fA-mG-fU-mC-mA-fU-mU-mC-mG-fU-mG-mC-mA-mC-mA-mUs-mGs-mG-3′ (SEQ ID NO: 1106), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

optionally wherein the oligonucleotide is a Dicer substrate.
 24. The double stranded RNAi oligonucleotide (dsRNAi) of claim 23, wherein the sense strand comprises the sequence and all of the modifications of 5′-mCs-mU-mC-mA-mA-mG-mG-fA-fU-fU-fU-mC-mA-mG-mU-mU-mA-mU-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 963), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fAs-fU-fA-mA-fC-mU-mG-fA-mA-mA-mU-fC-mC-mU-mU-mG-mA-mGs-mGs-mG-3′ (SEQ ID NO: 1051), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

optionally wherein the oligonucleotide is a Dicer substrate.
 25. The double stranded RNAi oligonucleotide (dsRNAi) of claim 23, wherein the sense strand comprises the sequence and all of the modifications of 5′-mUs-mC-mA-mA-mG-mG-mA-fU-fU-fU-fC-mA-mG-mU-mU-mA-mU-mA-mA-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 964), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fUs-fUs-fA-fU-mA-fA-mC-mU-fG-mA-mA-mA-fU-mC-mC-mU-mU-mG-mAs-mGs-mG-3′ (SEQ ID NO: 1052), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

optionally wherein the oligonucleotide is a Dicer substrate.
 26. The double stranded RNAi oligonucleotide (dsRNAi) of claim 23, wherein the sense strand comprises the sequence and all of the modifications of 5′-mAs-mG-mC-mA-mG-mC-mG-fU-fC-fC-fA-mC-mU-mC-mA-mG-mA-mG-mC-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1006), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fGs-fCs-fU-fC-mU-fG-mA-mG-fU-mG-mG-mA-fC-mG-mC-mU-mG-mC-mUs-mGs-mG-3′ (SEQ ID NO: 1094), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

optionally wherein the oligonucleotide is a Dicer substrate.
 27. The double stranded RNAi oligonucleotide (dsRNAi) of claim 23, wherein the sense strand comprises the sequence and all of the modifications of 5′-mAs-mU-mG-mU-mG-mC-mA-fC-fG-fA-fA-mU-mG-mA-mC-mU-mG-mU-mU-mA-mG-mC-mA-mG-mC-mC-mG-[ademA-GalNAc]-[ademA-GalNAc]-[ademA-GalNAc]-mG-mG-mC-mU-mG-mC-3′ (SEQ ID NO: 1018), and wherein the antisense strand comprises the sequence and all of the modifications of 5′-[MePhosphonate-4O-mUs]-fAs-fAs-fC-fA-mG-fU-mC-mA-fU-mU-mC-mG-fU-mG-mC-mA-mC-mA-mUs-mGs-mG-3′ (SEQ ID NO: 1106), wherein mC, mA, mG, and mU=2′-OMe ribonucleosides; fA, fC, fG, and fU=2′-F ribonucleosides; s=phosphorothioate, and wherein ademA-GalNAc=

optionally wherein the oligonucleotide is a Dicer substrate.
 28. A pharmaceutical composition comprising a double stranded RNAi oligonucleotide of claim 23, and a pharmaceutically acceptable carrier, delivery agent or excipient.
 29. A method of treating non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus, comprising administering to a patient in need thereof a double stranded RNAi oligonucleotide of claim
 23. 30. A method of treating non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), multiple sclerosis, or systemic lupus erythematosus, comprising administering to a patient in need thereof the pharmaceutical composition of claim
 28. 